Phenyl linked quinolinyl modulators of RORγt

ABSTRACT

The present invention comprises compounds of Formula I. 
                         
wherein:
 
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are defined in the specification.
 
     The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim  1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/053,773, filed on Oct. 15, 2013, now U.S. Pat. No. 9,403,816, issuedon Aug. 2, 2016, which is incorporated herein by reference.

FIELD OF THE INVENTION

The invention is directed to substituted quinoline compounds, which aremodulators of the nuclear receptor RORγt, pharmaceutical compositions,and methods for use thereof. More particularly, the RORγt modulators areuseful for preventing, treating or ameliorating an RORγt mediatedinflammatory syndrome, disorder or disease.

BACKGROUND OF THE INVENTION

Retinoic acid-related nuclear receptor gamma t (RORγt) is a nuclearreceptor, exclusively expressed in cells of the immune system, and a keytranscription factor driving Th17 cell differentiation. Th17 cells are asubset of CD4⁺ T cells, expressing CCR6 on their surface to mediatetheir migration to sites of inflammation, and dependent on IL-23stimulation, through the IL-23 receptor, for their maintenance andexpansion. Th17 cells produce several proinflammatory cytokinesincluding IL-17A, IL-17F, IL-21, and IL-22 (Korn, T., E. Bettelli, etal. (2009). “IL-17 and Th17 Cells.” Annu Rev Immunol 27: 485-517.),which stimulate tissue cells to produce a panel of inflammatorychemokines, cytokines and metalloproteases, and promote recruitment ofgranulocytes (Kolls, J. K. and A. Linden (2004). “Interleukin-17 familymembers and inflammation.” Immunity 21(4): 467-76; Stamp, L. K., M. J.James, et al. (2004). “Interleukin-17: the missing link between T-cellaccumulation and effector cell actions in rheumatoid arthritis” ImmunolCell Biol 82(1): 1-9). Th17 cells have been shown to be the majorpathogenic population in several models of autoimmune inflammation,including collagen-induced arthritis (CIA) and experimental autoimmuneencephalomyelitis (EAE) (Dong, C. (2006). “Diversification ofT-helper-cell lineages: finding the family root of IL-17-producingcells.” Nat Rev Immunol 6(4): 329-33; McKenzie, B. S., R. A. Kastelein,et al. (2006). “Understanding the IL-23-IL-17 immune pathway.” TrendsImmunol 27(1): 17-23.). RORγt-deficient mice are healthy and reproducenormally, but have shown impaired Th17 cell differentiation in vitro, asignificantly reduced Th17 cell population in vivo, and decreasedsusceptibility to EAE (Ivanov, II, B. S. McKenzie, et al. (2006). “Theorphan nuclear receptor RORgamma t directs the differentiation programof proinflammatory IL-17+ T helper cells.” Cell 126(6): 1121-33.). Micedeficient for IL-23, a cytokine required for Th17 cell survival, fail toproduce Th17 cells and are resistant to EAE, CIA, and inflammatory boweldisease (IBD) (Cua, D. J., J. Sherlock, et al. (2003). “Interleukin-23rather than interleukin-12 is the critical cytokine for autoimmuneinflammation of the brain.” Nature 421(6924): 744-8; Langrish, C. L., Y.Chen, et al. (2005). “IL-23 drives a pathogenic T cell population thatinduces autoimmune inflammation.” J Exp Med 201(2): 233-40; Yen, D., J.Cheung, et al. (2006). “IL-23 is essential for T cell-mediated colitisand promotes inflammation via IL-17 and IL-6.” J Clin Invest 116(5):1310-6.). Consistent with these findings, an anti-IL23-specificmonoclonal antibody blocks development of psoriasis-like inflammation ina murine disease model (Tonel, G., C. Conrad, et al. “Cutting edge: Acritical functional role for IL-23 in psoriasis.” J Immunol 185(10):5688-91).

In humans, a number of observations support the role of the IL-23/Th17pathway in the pathogenesis of inflammatory diseases. IL-17, the keycytokine produced by Th17 cells, is expressed at elevated levels in avariety of allergic and autoimmune diseases (Barczyk, A., W. Pierzchala,et al. (2003). “Interleukin-17 in sputum correlates with airwayhyperresponsiveness to methacholine.” Respir Med 97(6): 726-33; Fujino,S., A. Andoh, et al. (2003). “Increased expression of interleukin 17 ininflammatory bowel disease.” Gut 52(1): 65-70; Lock, C., G. Hermans, etal. (2002). “Gene-microarray analysis of multiple sclerosis lesionsyields new targets validated in autoimmune encephalomyelitis.” Nat Med8(5): 500-8; Krueger, J. G., S. Fretzin, et al. “IL-17A is essential forcell activation and inflammatory gene circuits in subjects withpsoriasis.” J Allergy Clin Immunol 130(1): 145-154 e9.). Furthermore,human genetic studies have shown association of polymorphisms in thegenes for Th17 cell-surface receptors, IL-23R and CCR6, withsusceptibility to IBD, multiple sclerosis (MS), rheumatoid arthritis(RA) and psoriasis (Gazouli, M., I. Pachoula, et al. “NOD2/CARD15,ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn'sdisease.” World J Gastroenterol 16(14): 1753-8, Nunez, C., B. Dema, etal. (2008). “IL23R: a susceptibility locus for celiac disease andmultiple sclerosis?” Genes Immun 9(4): 289-93; Bowes, J. and A. Barton“The genetics of psoriatic arthritis: lessons from genome-wideassociation studies.” Discov Med 10(52): 177-83; Kochi, Y., Y. Okada, etal. “A regulatory variant in CCR6 is associated with rheumatoidarthritis susceptibility.” Nat Genet 42(6): 515-9.).

Ustekinumab (Stelara®), an anti-p40 monoclonal antibody blocking bothIL-12 and IL-23, is approved for the treatment of adult patients (18years or older), with moderate to severe plaque psoriasis, who arecandidates for phototherapy or systemic therapy. Currently, monoclonalantibodies specifically targeting only IL-23, to more selectivelyinhibit the Th17 subset, are also in clinical development for psoriasis(Garber K. (2011). “Psoriasis: from bed to bench and back” Nat Biotech29, 563-566), further implicating the important role of the IL-23- andRORγt-driven Th17 pathway in this disease. Results from recent phase IIclinical studies strongly support this hypothesis, as anti-IL-17receptor and anti-IL-17 therapeutic antibodies both demonstrated highlevels of efficacy in patients with chronic psoriasis (Papp, K. A.,“Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.” NEngl J Med 2012 366(13): 1181-9; Leonardi, C., R. Matheson, et al.“Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaquepsoriasis.” N Engl J Med 366(13): 1190-9.). Anti-IL-17 antibodies havealso demonstrated clinically relevant responses in early trials in RAand uveitis (Hueber, W., Patel, D. D., Dryja, T., Wright, A. M.,Koroleva, I., Bruin, G., Antoni, C., Draelos, Z., Gold, M. H., Durez,P., Tak, P. P., Gomez-Reino, J. J., Foster, C. S., Kim, R. Y., Samson,C. M., Falk, N. S., Chu, D. S., Callanan, D., Nguyen, Q. D., Rose, K.,Haider, A., Di Padova, F. (2010) Effects of AIN457, a fully humanantibody to interleukin-17A, on psoriasis, rheumatoid arthritis, anduveitis. Sci Transl Med 2, 5272.).

All the above evidence supports inhibition of the Th17 pathway bymodulating RORγt activity as an effective strategy for the treatment ofimmune-mediated inflammatory diseases.

SUMMARY OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,        thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl,        pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl,        isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein        said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,        thiophenyl, benzoxazolyl, and pyrazolyl are optionally        substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl,        F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃,        or OCH₂OCH₃; and optionally substituted with up to two        additional substituents independently selected from the group        consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,        oxazolyl, isoxazolyl, and thiazolyl are optionally substituted        with one or two CH₃ groups; and wherein said azetidinyl is        optionally substituted with CO₂C(CH₃)₃, C(O)NH₂, CH₃, SO₂CH₃, or        C(O)CH₃;    -   R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide,        1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl,        oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,        N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,        N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl        piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,        N—C₍₁₋₂₎alkyl-piperidinyl (including N-methyl piperidin-4-yl),        thiazol-5-yl, 1-methyl imidazol-2-yl,        1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl        imidazol-5-yl; wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is        optionally substituted with up to two additional CH₃ groups, or        one substituent selected from the group consisting of SCH₃, and        Cl; and said pyridyl, and pyridyl-N-oxide are optionally        substituted with up to two substituents independently selected        from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, and        CH₃; and said thiazol-5-yl, oxazolyl, and isoxazolyl are        optionally substituted with up to two CH₃ groups; and said        1-methyl pyrazol-4-yl is optionally substituted with up to two        additional CH₃ groups;    -   R³ is H, OH, OCH₃, NHCH₃, N(CH₃)₂ or NH₂;    -   R⁴ is H, or F;    -   R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl,        N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl), N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl,        OCHF₂, 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;    -   R⁶ is 2-chloro-thiophen-5-yl, 1-methyl-pyrazol-4-yl, phenyl,        pyrimidinyl, or pyridyl, wherein said phenyl, pyrimidinyl, and        pyridyl are optionally substituted with SO₂CH₃, NHSO₂CH₃, CF₃,        F, Cl, —CN, OCH₃, or OCF₃;    -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃,        SO₂CH₃, OCHF₂, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A²,        OCH₂CH₂NA¹A², OCH₂CH₂NH₂, OC₍₁₋₃₎alkyl,        OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl,        pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl,        1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group;

-   -   A¹ is H or C₍₁₋₄₎alkyl (including CH₃);    -   A² is C₍₁₋₄₎alkyl (including CH₃), cyclopropyl,        C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or        OCH₃; or A¹ and A² may be taken together with their attached        nitrogen to form a ring selected from the group consisting of:

-   -   R_(a) is H, F, OCH₃, or OH;    -   R_(b) is CH₃, or phenyl;    -   R⁸ is H, CH₃, OCH₃, or F;    -   R⁹ is H, or F;        and pharmaceutically acceptable salts thereof;        provided that        (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-3-yl)methanamine,        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanamine,        (4-chlorophenyl)(3-(2,6-dichlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(2-(dimethylamino)pyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,        4-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)thiomorpholine        1,1-dioxide,        1-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one,        (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,        (4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol,        6-((3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile,        (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-4-yl)(6-methylpyridin-3-yl)methanol,        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol,        the second eluting enantiomer of        (4-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol,        and the second eluting enantiomer of        (4-chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol        (when purified on a chiralcel OD column) are excluded from the        embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I.

wherein:

-   -   R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,        thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl,        pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl,        isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein        said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl,        thiophenyl, benzoxazolyl, and pyrazolyl are optionally        substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl,        F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃,        or OCH₂OCH₃; and optionally substituted with up to two        additional substituents independently selected from the group        consisting of Cl, OCH₃, and CH₃; and wherein said triazolyl,        oxazolyl, isoxazolyl, and thiazolyl are optionally substituted        with one or two CH₃ groups; and wherein said azetidinyl is        optionally substituted with CO₂C(CH₃)₃, C(O)NH₂, CH₃, SO₂CH₃, or        C(O)CH₃;    -   R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide,        1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl,        oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,        N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,        N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl        piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,        N—C₍₁₋₂₎alkyl-piperidinyl (including N-methyl piperidin-4-yl),        thiazol-5-yl, 1-methyl imidazol-2-yl,        1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl        imidazol-5-yl; wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is        optionally substituted with up to two additional CH₃ groups, or        one substituent selected from the group consisting of SCH₃, and        Cl; and said pyridyl, and pyridyl-N-oxide are optionally        substituted with up to two substituents independently selected        from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, and        CH₃; and said thiazol-5-yl, oxazolyl, and isoxazolyl are        optionally substituted with up to two CH₃ groups; and said        1-methyl pyrazol-4-yl is optionally substituted with up to two        additional CH₃ groups;    -   R³ is H, OH, OCH₃, NHCH₃, N(CH₃)₂ or NH₂;    -   R⁴ is H, or F;    -   R⁵ is H, Cl, —CN, CF₃, SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl,        N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl), N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl,        OCHF₂, 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;    -   R⁶ is 2-chloro-thiophen-5-yl, 1-methyl-pyrazol-4-yl, phenyl,        pyrimidinyl, or pyridyl, wherein said phenyl, pyrimidinyl, and        pyridyl are optionally substituted with SO₂CH₃, NHSO₂CH₃, CF₃,        F, Cl, —CN, OCH₃, or OCF₃;    -   R⁷ is H, Cl, —CN, C₍₁₋₄₎alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃,        SO₂CH₃, OCHF₂, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A²,        OCH₂CH₂NA¹A², OCH₂CH₂NH₂, OC₍₁₋₃₎alkyl,        OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl,        pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl,        1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group;

-   -   A¹ is H or C₍₁₋₄₎alkyl (including CH₃);    -   A² is C₍₁₋₄₎alkyl (including CH₃), cyclopropyl,        C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or        OCH₃; or A¹ and A² may be taken together with their attached        nitrogen to form a ring selected from the group consisting of:

-   -   R_(a) is H, F, OCH₃, or OH;    -   R_(b) is CH₃, or phenyl;    -   R⁸ is H, CH₃, OCH₃, or F;    -   R⁹ is H, or F;        and pharmaceutically acceptable salts thereof;        provided that        (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-3-yl)methanamine,        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanamine,        (4-chlorophenyl)(3-(2,6-dichlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(2-(dimethylamino)pyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,        4-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)thiomorpholine        1,1-dioxide,        1-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one,        (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol,        (4-chloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,        (4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol,        6-((3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile,        (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-4-yl)(6-methylpyridin-3-yl)methanol,        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol,        the second eluting enantiomer of        (4-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol,        and the second eluting enantiomer of        (4-chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol        (when purified on a chiralcel OD column) are excluded from the        embodiment.

In another embodiment of the invention:

-   -   R¹ is imidazolyl, thiazolyl, pyridyl, pyrimidinyl, or phenyl;        wherein said pyridyl, and said phenyl are optionally substituted        with —CN, CF₃, F, or Cl; and wherein said imidazolyl, and        thiazolyl are optionally substituted with one or two CH₃ groups;    -   R² is 1-methyl-1,2,3-triazol-5-yl, N-acetyl piperidin-4-yl,        N-Boc-piperidin-4-yl, N-methyl piperidin-4-yl1-H-piperidin-4-yl,        oxazol-2-yl, 2,4-dimethyl thiazol-5-yl, 1-methyl imidazol-2-yl,        1-methyl-imidazol-5-yl, or pyridyl; wherein said pyridyl is        optionally substituted with CF₃;    -   R³ is H, OH;    -   R⁴ is H;    -   R⁵ is H, Cl, —CN, C₍₁₋₄₎alkyl, OC₍₁₋₂₎alkyl, SCH₃, N(CH₃)₂, or        N(CH₃)OCH₃;    -   R⁶ is 2-chloro-thiophen-5-yl, 1-methyl-pyrazol-4-yl, phenyl,        pyrimidinyl, or pyridyl, wherein said phenyl, pyrimidinyl, and        pyridyl are optionally substituted with SO₂CH₃, NHSO₂CH₃, CF₃,        Cl, —CN, OCF₃, or OCH₃;    -   R⁷ is Cl, —CN, CF₃, SCH₃, OCH₂CF₃, NA¹A², N(CH₃)CH₂CH₂NA¹A²,        OC₍₁₋₃₎alkyl, OCH₂CH₂OCH₃, OCH₂CH₂NA¹A², or OCH₂CH₂NH₂;    -   A¹ is H, or CH₃;    -   A² is OCH₃, CH₃, CH₂CH₂OH, C(O)C₍₁₋₂₎alkyl, or CH₂CH₂OCH₃; or A¹        and A² may be taken together with their attached nitrogen to        form a ring selected from the group consisting of:

-   -   R⁸ is H, or CH₃;    -   R⁹ is H;        and pharmaceutically acceptable salts thereof;        provided that        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,        6-(3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile,        (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol,        (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol,        (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol,        (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol,        the second eluting enantiomer of        (4-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol,        and the second eluting enantiomer of        (4-chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol        (when purified on a chiralcel OD column) are excluded from the        embodiment.

Another embodiment of the invention is a compound selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention comprises a compound of Formula Iand a pharmaceutically acceptable carrier.

The present invention also provides a method for treating orameliorating an RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of preventing, treating orameliorating a syndrome, disorder or disease, wherein said syndrome,disorder or disease is selected from the group consisting of: ophthalmicdisorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis,psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn'sDisease, ulcerative colitis, ankylosing spondylitis, nephritis, organallograft rejection, fibroid lung, systic fibrosis, renal insufficiency,diabetes and diabetic complications, diabetic nephropathy, diabeticretinopathy, diabetic retinitis, diabetic microangiopathy, tuberculosis,chronic obstructive pulmonary disease, sarcoidosis, invasivestaphylococcia, inflammation after cataract surgery, allergic rhinitis,allergic conjunctivitis, chronic urticaria, systemic lupuserythematosus, asthma, allergic asthma, steroid resistant asthma,neutrophilic asthma, periodontal diseases, periodonitis, gingivitis, gumdisease, diastolic cardiomyopathies, cardiac infarction, myocarditis,chronic heart failure, angiostenosis, restenosis, reperfusion disorders,glomerulonephritis, solid tumors and cancers, chronic lymphocyticleukemia, chronic myelocytic leukemia, multiple myeloma, malignantmyeloma, Hodgkin's disease, and carcinomas of the bladder, breast,cervix, colon, lung, prostate, or stomach comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, and ulcerative colitiscomprising administering to a subject in need thereof an effectiveamount of a compound of Formula I or a form, composition or medicamentthereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, Crohn's disease, neutrophilic asthma, steroidresistant asthma, multiple sclerosis, systemic lupus erythematosus, andulcerative colitis comprising administering to a subject in need thereofan effective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: rheumatoid arthritis,and psoriasis comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, in a subject in need thereof comprisingadministering to the subject an effective amount of the compound ofFormula I or composition or medicament thereof in a combination therapywith one or more anti-inflammatory agents, or immunosuppressive agents,wherein said syndrome, disorder or disease is selected from the groupconsisting of: rheumatoid arthritis, and psoriasis.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is rheumatoid arthritis, comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriasis comprising administering to a subject in needthereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is chronic obstructive pulmonary disorder comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I or a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is psoriatic arthritis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is ankylosing spondylitis comprising administering to a subjectin need thereof an effective amount of a compound of Formula I or aform, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is Crohn's disease comprising administering to a subject in needthereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is ulcerative colitis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is neutrophilic asthma comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is steroid resistant asthma comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is multiple sclerosis comprising administering to a subject inneed thereof an effective amount of a compound of Formula I or a form,composition or medicament thereof.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is systemic lupus erythematosus comprising administering to asubject in need thereof an effective amount of a compound of Formula Ior a form, composition or medicament thereof.

The invention also relates to methods of modulating RORγt activity in amammal by administration of an effective amount of at least one compoundof Formula I.

The present invention provides a method of treating or ameliorating asyndrome, disorder or disease, wherein said syndrome, disorder ordisease is selected from the group consisting of: inflammatory boweldiseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonarydisorder, psoriatic arthritis, ankylosing spondylitis, neutrophilicasthma, steroid resistant asthma, multiple sclerosis, and systemic lupuserythematosus comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel disease, wherein said inflammatory bowel disease isCrohn's disease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

The present invention provides a method of treating or ameliorating aninflammatory bowel diseases, wherein said inflammatory bowel disease isulcerative colitis comprising administering to a subject in need thereofan effective amount of a compound of Formula I or a form, composition ormedicament thereof.

DEFINITIONS

The term “administering” with respect to the methods of the invention,means a method for therapeutically or prophylactically preventing,treating or ameliorating a syndrome, disorder or disease as describedherein by using a compound of Formula I or a form, composition ormedicament thereof. Such methods include administering an effectiveamount of said compound, compound form, composition or medicament atdifferent times during the course of a therapy or concurrently in acombination form. The methods of the invention are to be understood asembracing all known therapeutic treatment regimens.

The term “subject” refers to a patient, which may be an animal,typically a mammal, typically a human, which has been the object oftreatment, observation or experiment and is at risk of (or susceptibleto) developing a syndrome, disorder or disease that is associated withabberant RORγt expression or RORγt overexpression, or a patient with aninflammatory condition that accompanies syndromes, disorders or diseasesassociated with abberant RORγt expression or RORγt overexpression.

The term “effective amount” means that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human, that is being sought by aresearcher, veterinarian, medical doctor, or other clinician, whichincludes preventing, treating or ameliorating the symptoms of asyndrome, disorder or disease being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl. Any alkyl group may be optionally substituted withone OCH₃, one OH, or up to two fluorine atoms.

The term “C_((a-b))” (where a and b are integers referring to adesignated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl,alkoxy or cycloalkyl radical or to the alkyl portion of a radical inwhich alkyl appears as the prefix root containing from a to b carbonatoms inclusive. For example, C₍₁₋₄₎ denotes a radical containing 1, 2,3 or 4 carbon atoms.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic or bicyclic hydrocarbon ring radical derived by the removalof one hydrogen atom from a single ring carbon atom. Typical cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Additionalexamples include C₍₃₋₆₎cycloalkyl, C₍₅₋₈₎cycloalkyl,decahydronaphthalenyl, and 2,3,4,5,6,7-hexahydro-1H-indenyl. Anycycloalkyl group may be optionally substituted with one OCH₃, one OH, orup to two fluorine atoms.

As used herein, the term “thiophenyl” is intended to describe theradical formed by removing a hydrogen atom from the molecule with thestructure:

Pharmaceutically Acceptable Salts

Pharmaceutically acceptable acidic/anionic salts include, and are notlimited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate and triethiodide. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are notlimited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (alsoknown as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”),ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calciumhydroxide, chloroprocaine, choline, choline bicarbonate, cholinechloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium,LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, sodium, sodium carbonate,sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine or zinc.

Methods of Use

The present invention is directed to a method for preventing, treatingor ameliorating a RORγt mediated inflammatory syndrome, disorder ordisease comprising administering to a subject in need thereof aneffective amount of a compound of Formula I or a form, composition ormedicament thereof.

Since RORγt is an N-terminal isoform of RORγ, it is recognized thatcompounds of the present invention which are modulators of RORγt arelikely to be modulators of RORγ as well. Therefore the mechanisticdescription “RORγt modulators” is intended to encompass RORγ modulatorsas well.

When employed as RORγt modulators, the compounds of the invention may beadministered in an effective amount within the dosage range of about 0.5mg to about 10 g, preferably between about 0.5 mg to about 5 g, insingle or divided daily doses. The dosage administered will be affectedby factors such as the route of administration, the health, weight andage of the recipient, the frequency of the treatment and the presence ofconcurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for compounds of the present invention or apharmaceutical composition thereof will vary according to the desiredeffect. Therefore, optimal dosages to be administered may be readilydetermined by one skilled in the art and will vary with the particularcompound used, the mode of administration, the strength of thepreparation, and the advancement of the disease condition. In addition,factors associated with the particular subject being treated, includingsubject age, weight, diet and time of administration, will result in theneed to adjust the dose to an appropriate therapeutic level. The abovedosages are thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

The compounds of Formula I may be formulated into pharmaceuticalcompositions comprising any known pharmaceutically acceptable carriers.Exemplary carriers include, but are not limited to, any suitablesolvents, dispersion media, coatings, antibacterial and antifungalagents and isotonic agents. Exemplary excipients that may also becomponents of the formulation include fillers, binders, disintegratingagents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts which are formed from inorganic or organic acids or bases.Examples of such acid addition salts include acetate, adipate, benzoate,benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride,hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate,pivalate, propionate, succinate, sulfate and tartrate. Base saltsinclude ammonium salts, alkali metal salts such as sodium and potassiumsalts, alkaline earth metal salts such as calcium and magnesium salts,salts with organic bases such as dicyclohexylamino salts and salts withamino acids such as arginine. Also, the basic nitrogen-containing groupsmay be quaternized with, for example, alkyl halides.

The pharmaceutical compositions of the invention may be administered byany means that accomplish their intended purpose. Examples includeadministration by parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, buccal or ocular routes. Alternatively orconcurrently, administration may be by the oral route. Suitableformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form, for example, water-solublesalts, acidic solutions, alkaline solutions, dextrose-water solutions,isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

The present invention also encompasses a method of making apharmaceutical composition comprising mixing a pharmaceuticallyacceptable carrier with any of the compounds of the present invention.Additionally, the present invention includes pharmaceutical compositionsmade by mixing a pharmaceutically acceptable carrier with any of thecompounds of the present invention.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopepolymorphs and solvates of the compounds of the present invention. Thus,in the methods of treatment of the present invention, the term“administering” shall encompass the means for treating, ameliorating orpreventing a syndrome, disorder or disease described herein with thecompounds of the present invention or a polymorph or solvate thereof,which would obviously be included within the scope of the inventionalbeit not specifically disclosed.

In another embodiment, the invention relates to a compound as describedin Formula I for use as a medicament.

In another embodiment, the invention relates to the use of a compound asdescribed in Formula I for the preparation of a medicament for thetreatment of a disease associated with an elevated or aberrant RORγtactivity.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of Formula I, shall comprise all isotopes and isotopic mixturesof said element, either naturally occurring or synthetically produced,either with natural abundance or in an isotopically enriched form. Forexample, a reference to hydrogen includes within its scope ¹H, ²H (D),and ³H (T). Similarly, references to carbon and oxygen include withintheir scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopesmay be radioactive or non-radioactive. Radiolabelled compounds ofFormula I may comprise a radioactive isotope selected from the group of³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.Preferably, the radioactive isotope is selected from the group of ³H,¹¹C and ¹⁸F.

Some compounds of the present invention may exist as atropisomers.Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. It is to be understoodthat all such conformers and mixtures thereof are encompassed within thescope of the present invention.

Where the compounds according to this invention have at least onestereocenter, they may accordingly exist as enantiomers ordiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

ABBREVIATIONS

Herein and throughout the application, the following abbreviations maybe used.

-   Å angstrom-   Ac acetyl-   Ac₂O acetic anhydride-   Boc tert-butyloxy carbonyl-   BHT butylated hydroxytoluene-   br broad-   Bu butyl-   n-BuLi n-butyl lithium-   t-BuOH tert-butanol-   d doublet-   dba dibenzylideneacetone-   DCE dichloroethane-   DCM dichloromethane-   Dess-Martin periodinane    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one-   DIEA N,N-diisopropylethylamine-   DMA dimethylacetamide-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   dppf (diphenylphosphino)ferrocene-   Eaton's Reagent 7.7 wt % phosphorus pentoxide solution in    methanesulfonic acid-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   ESI electrospray ionization-   Et ethyl-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethyl alcohol-   FCC flash column chromatography-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium    hexafluorophosphate-   HPLC high pressure liquid chromatography-   Hunig's base N, N-diisopropylethylamine-   Hz hertz-   i-PrOH isopropyl alcohol-   KHMDS potassium bis(trimethylsilyl)amide-   LCMS liquid chromatography-mass spectrometry-   LDA lithium diisopropylamide-   m multiplet-   M molar (moles/liter)-   mCPBA 3-chloroperbenzoic acid-   Me methyl-   Meldrum's acid 2,2-dimethyl-1,3-dioxane-4,6-dione-   MeOH methanol-   MeONa sodium methoxide-   MHz megahertz-   min minutes-   mL milliliters-   MS mass spectrometry-   MTBE methyl tertiary butyl ether-   m/z mass to charge ratio-   nm nanometers-   NaOiPr sodium isopropoxide-   NB S N-bromosuccinimide-   NMP 1-methyl-2-pyrrolidinone-   NMR nuclear magnetic resonance-   Ph phenyl-   PPA polyphosphoric acid-   ppm parts per million-   Pr propyl-   q quartet-   RP-HPLC reverse phase high pressure liquid chromatography-   s singlet-   t triplet-   TBAF tetrabutylammonium fluoride-   TEA triethylamine-   TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   UV ultra-violet-   X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl    General Schemes:

Compounds of Formula I in the present invention can be synthesized inaccordance with the general synthetic methods known to those who areskilled in the art. The following reaction schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

Scheme 1 describes the preparation of 6-bromo or 6-iodo-quinolines ofFormula IV by various methods (path 1 to 4). In path 1, cyclization of4-haloanilines II with commercially available 2-substituted malonicacids III can be done in refluxing phosphorus oxychloride to provide6-haloquinolines IV, wherein R⁵ and R⁷ are Cl. Nucleophilic displacementof 2-chloro substitution with sodium methoxide in hot MeOH or toluene(Alan Osborne et. al. J. Chem. Soc. Perkin Trans. 1 (1993) 181-184 andJ. Chem. Research (S), 2002, 4) gives 6-halo-2-methoxyquinolines IV.Path 2 illustrates the cyclization of amides VI, derived from acylationof 4-haloanilines II with substituted acid chlorides V (acid chlorides Vare either commercially available or prepared from the correspondingcarboxylic acid precursors by procedures known to those skilled in theart), in the presence of DMF in hot phosphorus oxychloride to generate6-haloquinolines IV, wherein R⁵ is H and R⁷ is Cl. In path 3, methyl2-aminobenzoates VII can undergo acylation with acid chlorides V to forman amide intermediate, which can be further treated with a base, such assodium ethoxide or lithium bis(trimethylsilyl)amide, to afford6-halo-4-hydroxyquinolin-2(1H)-ones VIII Conversion ofhydroxyquinolin-2(1H)-ones VIII to 2,4-dichloroquinolines IV can becarried out in refluxing phosphorus oxychloride. Path 4 describes thecondensation of anilines II and aldehydes IX in ethanol to form compoundX which can be further cyclized in polyphosphoric acid at hightemperatures to give quinolinones XI. Conversion to the4-chloroquinolines IV wherein R⁷ is H can be accomplished in phosphorusoxychloride as previously described.

Scheme 2 illustrates the synthesis leading to 6-bromo or6-iodoquinolines of Formula IV wherein R⁵ is Cl and R⁷ is CF₃ (path 1),and 6-iodoquinolines of Formula IV where R⁵ and R⁷ are CF₃ (path 2). Inpath 1, cyclization of 2-aminobenzoic acids XII with1,1,1-trifluoropropan-2-ones XIII in Eaton's reagent at elevatedtemperatures yields 4-hydroxy-2-trifluoromethylquinolines XIV, whichupon heating in phosphorus oxychloride at temperatures between 100-120°C. gives 6-bromo or 6-iodoquinolines IV, wherein R⁵ is Cl and R⁷ is CF₃.6-Iodo-2,4-bis(trifluoromethyl)quinolines IV can be formed by thereaction sequence illustrated in path 2. Treatment of1-bromo-4-fluorobenzenes XV with lithium diisopropylamide at −78° C.followed by addition of ethyl trifluoroacetate provides2-fluorophenyl-2,2,2-trifluoroethanones XVI. Anilines XVII can beprepared by displacing 2-fluoro in XVI with sodium azide followed byreduction with tin (II) chloride dihydrate. Cyclization of XVII with1,1,1-trifluoropropan-2-ones XIII in the presence of tributylamine in apolar solvent, such as DMF or DMSO, at high temperatures can provide6-bromo-2,4-bis(trifluoromethyl)quinolines IV. The6-iodo-2,4-bis(trifluoromethyl)quinolines IV can then be subsequentlyobtained by conversion of 6-bromoquinoline IV, where R⁵ and R⁷ are CF₃,with NaI, CuI, and N,N′-dimethylethylenediamine in t-BuOH at hightemperatures under microwave conditions.

Scheme 3 illustrates synthetic routes (path 1 to 6) to ketones ofFormula XXI wherein R¹ and R² are as described in the detaileddescription of the invention. In path 1, Weinreb amide XX can beprepared from acids XIX by reacting with N,O-dimethylhydroxylaminehydrochloride and 1,1-carbonyldiimidazole or withN,O-dimethylhydroxylamine hydrochloride in the presence of a base suchas triethylamine or Hunig's base and a coupling reagent such as EDCI.The amides XX can be further treated with Grignard reagents such asR²MgX (X is Br or Cl) that can be obtained commercially or preformed bytreatment of R²Z with organometallic reagents such as i-PrMgCl or EtMgClin THF. Alternatively, Weinreb amides XX can be obtained from acylchlorides XXII and N,O-dimethylhydroxylamine hydrochloride by usingtriethylamine or pyridine as a base. 1-Methyl-1H-imidazole can betreated with one equivalent of n-BuLi and one equivalent ofchlorotriethylsilane at −78° C. followed by an additional equivalent ofn-BuLi, to which the Weinreb amides XX can be added to yield ketones XXIwherein R² is imidazolyl (path 2).

In path 3, halogen and metal exchange of bromides or iodides XXIV withi-PrMgCl.LiCl or n-BuLi, followed by addition of aldehydes XXIII affordsalcohols XXV. Oxidation of XXV with Dess-Martin periodinane or MnO₂ canprovide ketones XXI. In path 4, ketones XXI, where R² is triazolyl, canbe prepared by treatment of 1-methyl-1H-1,2,3-triazole with n-BuLifollowed by reaction with aldehydes XXIII to yield alcohols XXV, whichcould undergo oxidation with Dess-Martin periodinane or MnO₂. Path 5exemplifies the preparation of symmetrical ketones XXI, wherein R¹ andR² are the same. As illustrated, an aryl or heteroaryl group containingan acidic proton XXXIX (Y=R¹ or R²) can be deprotonated in the presenceof a strong base such as n-butyllithium once solubilized in a preferredsolvent such as tetrahydrofuran at temperatures between 0 and −78° C.then added in excess to ethyl methoxy(methyl)carbamate to provideketones XXI wherein R¹ and R² are the same. Aryl or heteroaryl bromideor iodide XL can also be lithiated through a lithium/halogen exchangewith n-butyllithium before adding in excess to ethylmethoxy(methyl)carbamate as previously described to provide symmetricalketones XXI. Path 6, which employs palladium catalyzed cross-coupling ofarylboronic acids XXXVII with acid chlorides XXXVIII using K₃PO₄ as abase and (Ph₃P)₂PdCl₂ as a catalyst in a high boiling non-polar solventsuch as toluene, can also be used to generate ketones XXI.

Synthesis leading to intermediate ketones XXVII may also be achieved viachemical routes shown in Scheme 4. In path 1, treatment of 6-bromo or6-iodoquinolines IV with n-BuLi at −78° C. followed by addition ofaldehydes XXIII provides secondary alcohol quinolines XXVI, which can beoxidized to ketones XXVII with Dess-Martin periodinane or MnO₂.Alternatively, ketones XXVII may also be prepared by treatment of6-haloquinolines IV with n-BuLi at −78° C. followed by quenching withDMF affording carboxaldehydes XXVIII. Ketones XXVII can be obtained in atwo-step process by addition of aldehyde XXVIII to a reaction mixture ofaryl iodides or bromides XXIX and i-PrMgCl.LiCl followed by oxidationwith MnO₂ (path 2).

As illustrated in path 3, a one-pot reaction of aldehydes XXX andGrignard reagents such as R¹—MgCl XVIII followed by treatment withi-PrMgCl and addition of 2,2,2-trifluoro-N-methoxy-N-methylacetamideyields hydroxyl compounds XXXI. The hydroxyl group can be oxidized usingbleach and TEMPO. Fluoro displacement can then be achieved with ammoniain hot DMSO to provide anilines XXXII. In the presence ofbenzenesulfonic acid, condensation of anilines XXXII and2-(methylimino)butanamides XXXIII in hot DMSO furnishes ketoquinolinesXXVII wherein R⁵ is CF₃ and R⁷ is CONHMe.

Scheme 5 illustrates synthetic routes leading to compounds of Formula I(path 1 to 3). As illustrated in path 1, a mixture of the 6-bromo or6-iodoquinolines IV in an appropriate solvent such as THF can be eitherpremixed with the ketones XXI at −78° C. followed by addition of n-BuLior can be pretreated with n-BuLi at −78° C. prior to the addition of theketones XXI to afford the tertiary alcohols of Formula I, wherein R³ isOH. In path 2, 6-iodoquinolines IV can be treated with i-PrMgCl followedby addition of ketone XXI to yield compounds of Formula I wherein R³ isOH. As shown in path 3, halogen-metal exchange of aryl halides (iodideor bromide) XXIV with an organometallic reagent, such as n-BuLi,i-PrMgCl.LiCl, or EtMgCl, at an appropriate temperature, such as −78° C.or 0° C., followed by reaction with ketones XXVII may afford tertiaryalcohol quinolines of Formula I. Compounds of Formula I wherein R² isN-Boc piperdinyl can be deprotected under acidic conditions usingstandard procedures known in the art then further functionalized onnitrogen by treatment with an anhydride or acylating agent such asacetylchloride to provide compounds of Formula I wherein R² is N-acetylpiperidin-4-yl.

Scheme 6 illustrates methods used to synthesize compounds of Formula Iwherein either the chlorine at R⁷ or at both R⁵ and R⁷ positions arereplaced with nitrogen, oxygen, sulfur or alkyl groups. In path 1, 4 and5, nucleophilic displacement of 2,4-dichloroquinolines I (R⁵ and R⁷ areCl) with NaO(alkyl), NaS(alkyl), such as NaOMe, NaSMe, NaOEt, orNaO^(i)Pr, in an appropriate solvent, such as MeOH, EtOH, i-PrOH or DMFat elevated temperatures or with substituted hydroxy reagents such as2-methoxyethanol, 2,2,2-trifluoroethanol or amine substituted hydroxylreagents in the presence of a base like sodium hydride in a non-polarsolvent such as toluene provides compounds of Formula I wherein R⁵ is Cland R⁷ is O(alkyl), S(alkyl), O(CH₂)₂OCH₃, OCH₂CF₃, or O(CH₂)₂NA¹A²wherein A¹ and A² are defined in the detailed description of theinvention and compounds of Formula I wherein R⁵ and R⁷ are O(alkyl) orS(alkyl). Likewise, nucleophilic displacement of 2,4-dichloroquinolinesI (R⁵ and R⁷ are Cl) with primary or secondary alkyl amines, heterocycleamines, or N, O-dimethylhydroxylamine in polar solvents such as MeOH,EtOH, or Et₂NCHO, or DMF provides quinolines of Formula I (path 2)wherein R⁵ is NH(alkyl), N(alkyl)₂, N(CH₃)OCH₃, or Cl, and R⁷ isNH(alkyl), N(alkyl)₂, N(CH₃)OCH₃, NA¹A², NHC₍₂₋₃₎alkylNA¹A² orN(CH₃)C₍₂₋₄₎alkylNA¹A², wherein A¹ and A² are as defined above.Replacement of chlorine at positions 2 and 4 of quinolines I (R⁵ and R⁷are Cl) with alkyl groups could be carried out using Zn(alkyl)₂ in thepresence of K₂CO₃ and a palladium catalyst, such as PdCl₂(dppf), toafford 2-alkyl and 2,4-dialkylquinolines I (path 3).

Synthetic routes to compounds of Formula I, wherein R⁵ is Cl or CN, andR⁷ is CN or aryl, are illustrated in Scheme 7. In path 1, cyanation ofthe 2,4-dichloroquinolines I with Zn(CN)₂ in the presence of Zn, apalladium catalyst, such as Pd₂(dba)₃, and a ligand, such as dppf orX-phos, at high temperatures can provide 2-CN and 2,4-diCN quinolines I.The 2,4-dichloroquinolines I can also undergo a Suzuki reactions withArB(OH)₂ or ArB(OR)₂ and a palladium catalyst, such as PdCl₂(dppf),yielding compounds of Formula I wherein R⁷ is phenyl, substituted phenyland five or six-membered heteroaryls such as furan, pyridine,pyridazine, pyrazine, pyrimidine, pyrrol, pyrazole or imidazole (path2).

As illustrated in Scheme 8, compounds of Formula I wherein R⁵ is achlorine can be further substituted by treatment with alkylboronic acidsor esters under Suzuki reaction conditions (path 1), with sodiumalkoxides (path 2), or with zinc cyanide (path 3) using conditionspreviously described to provide compounds of Formula I wherein R⁵ isalkyl, O(alkyl) or CN and R⁷ is as described above.

In Scheme 9, tertiary alcohols I can be treated with base, such as NaH,and alkylated with MeI in DMF to provide compounds of Formula I whereinR³ is OMe.

Synthetic routes to compounds of Formula I, wherein R³ is NH₂, areillustrated in Scheme 10. Ketimines XXXV may be prepared by Ti(OEt)₄mediated condensation of ketones XXI with 2-methylpropane-2-sulfinamidein refluxing THF. Addition of n-BuLi to the reaction mixture ofketimines XXXV and 6-bromo or 6-iodoquinolines IV at −78° C. followed bycleavage of tert-butanesulfinyl group with HCl in MeOH liberates aminesI. Alternatively, compounds of Formula I, wherein R³ is OH, can betreated with sodium hydride followed by addition of acetic anhydride oracetyl chloride and stirred at room temperature over a 24 to 72 hourperiod to provide the intermediate acetate wherein R³ is OAc. Theacetate can then be combined with a solution of ammonia in methanol andheated at temperatures between 60 and 85° C. to provide compounds ofFormula I, wherein R³ is NH₂.

As shown in Scheme 11, the quinolines of Formula I wherein R⁷ is CN canbe hydrolyzed as described in US20080188521 by treatment with sodiumcarbonate and hydrogen peroxide to provide compounds of Formula Iwherein R⁷ is CONH₂ (path 1) or can be treated with a strong acid likeHCl to convert CN to a carboxylic acid XXXIV (path 2). Once formed theacid can be further coupled to substituted amines using appropriatedcoupling reagents such as EDCI or HATU in the presence of a base such astriethylamine or Hunig's base to provide compounds of Formula I whereinR⁷ is CONA¹A².

Synthesis of compounds of Formula I, wherein R⁷ is anaminoalkylaminomethylene or an aminoalkoxymethylene can be prepared from2-methylquinolines as shown in Scheme 12. Bromination of2-methylquinolines of Formula I can be accomplished withN-bromosuccinimide in acetic acid at elevated temperatures as describedin WO2010151740, to provide the methylbromide intermediate XXXVI.Nucleophilic displacement of the bromide under basic conditions usingprocedures known in the art could afford compounds of Formula I whereinR⁷ is —CH₂NHC₍₂₋₃₎alkylNA¹A² or CH₂N(CH₃)C₍₂₋₃₎alkylNA¹A² (path 1) orCH₂OC₍₂₋₃₎alkylNA¹A² (path 2) and A¹ and A² are defined above.

Compounds of Formula I wherein R¹, R² or R⁶ are pyridyl can be treatedwith m-chloroperbenzoic acid in a chlorinated solvent at ambient to 40°C. to form the pyridyl-N-oxides of Formula I.

As shown in Scheme 13, compounds of the Formula I wherein R³ is H can beprepared by treating compounds of Formula I wherein R³ is OH with ahydride source such as triethylsilane and an acid such astrifluoroacetic acid in a solvent such as dichloromethane at roomtemperature or with heating (WO2009091735).

Scheme 14 outlines alternative synthetic methods to compounds of FormulaI. Acylation of methyl 2-aminobenzoates VII (path 1) or2-trifluoroketoanilines XVII (path 2) with benzyloxyacetyl chloride inthe presence of a base such as triethylamine in a solvent such asdichloromethane can afford amides XLI and XLV respectively. Amides XLIand XLV can undergo an intramolecular cyclization reaction with a basesuch as potassium bis(trimethylsilyl)amide in a solvent such astetrahydrofuran to provide the intermediate 6-haloquinolin-2(1H)-oneswhich can be converted with phosphorus oxychloride, as previouslydescribed, to compounds of Formula IV wherein R⁵ and R⁷ is Cl (resultingfrom path 1) and R⁵ is CF₃ and R⁷ is Cl (resulting from path 2). Thecoupling of 6-haloquinolines IV and ketones of Formula XXI to introduceR¹ and R² followed by displacement of the 2 or 4-chloro using procedurespreviously described provides quinolines of Formula XLII wherein R¹, R²,R⁵ and R⁷ are defined in the detailed description of the invention.Palladium-catalyzed hydrogenation of compounds of Formula XLII that aresubstituted with a benzyloxy at C-3 can provide intermediatequinolin-3-ols XLIII. The quinolin-3-ols XLIII can be converted into thecorresponding triflates XLIV with trifluoromethanesulfonic acid in thepresence of a base, such as pyridine, in a solvent such asdichloromethane. The triflates XLIV can be converted into compounds ofFormula I, wherein R⁶ is aryl or heteroaryl as defined above, by apalladium-catalyzed cross coupling with organoboron reagents of theformula R⁶B(OR)₂ in the presence of a base, such as potassium carbonate,in a solvent mixture such as 1,4-dioxane/water.

EXAMPLES

Compounds of the present invention can be prepared by methods known tothose who are skilled in the art. The following examples are only meantto represent examples of the invention and are in no way meant to be alimit of the invention.

Intermediate 1: Step a tert-Butyl4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylate

A solution of 5-bromo-1-methyl-1H-imidazole (25.0 g, 155 mmol; driedover 3 Å molecular sieves, then filtered) in DCM (310 mL) was stirred inan ice bath while iPrMgCl (72 mL, 2.01 M solution in THF, 145 mmol) wasadded rapidly dropwise under argon via pressure-equalizing additionfunnel. Residual iPrMgCl was rinsed down with 50 mL THF, and the icebath was removed and the reaction stirred for 25 minutes. A solution oftert-butyl 4-formylpiperidine-1-carboxylate (27.6 g, 130 mmol) in THF(65 mL) was added dropwise over ˜5 minutes via pressure-equalizingaddition funnel at room temperature. After stirring 1 hour at roomtemperature, the yellow mixture was quenched with 5 M aqueous NH₄Cl (250mL) in one portion. The organic layer was dried (Na₂SO₄), filtered, andconcentrated to provide the crude title compound as a clear light amberoil.

Intermediate 1: Step b tert-Butyl4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate

A homogeneous solution of tert-butyl4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylate(32.2 g, 109 mmol, Intermediate 1: step a) in 1,4-dioxane (436 mL) wastreated with MnO₂ (47.6 g, 547 mmol) and stirred at 100° C. open to theair overnight (17 hours). Since the reaction was only ˜50% complete byNMR, the reaction was cooled to room temperature and additional MnO₂ wasadded (48.0 g, 552 mmol) and the reaction stirred open to the air at100° C. for 6.5 hours, then at room temperature for 18 days, thenfiltered through a pad of Celite® and the black filter cake washed withEtOAc. The crude filtrate was treated with a third portion of MnO₂ (28.5g, 327 mmol) and stirred at room temperature overnight. The reaction wasthen filtered as above and concentrated to provide the crude titlecompound as a clear dark yellow oil. This oil was purified by FCC withan EtOAc to 50% acetone/EtOAc gradient to provide the title compound asa clear dark yellow oil.

Intermediate 1: Step c1-(4-(1-Methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone

A homogeneous yellow solution of tert-butyl4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate (10.1 g,34.4 mmol, Intermediate 1: step b) in DCM (172 mL) was treated with TFA(26.4 mL, 344 mmol) and stirred at room temperature for 2.5 hours. Thereaction was concentrated from toluene (2×100 mL), and the resultingclear light amber residue was taken up in DCM (344 mL) and TEA (23.9 mL,172 mmol). Acetic anhydride (3.91 mL, 41.3 mmol) was added dropwise andthe reaction stirred at room temperature for 1 hour. The reaction wasconcentrated under high vacuum and the residue was purified by FCC using95:5 DCM/MeOH with 2% TEA as eluent. The combined fractions wereconcentrated, dissolved in DCM (200 mL), and washed with water (2×200mL) to remove TEA. The organic layer was dried (Na₂SO₄), filtered, andconcentrated. The residue was triturated with MTBE (75 mL) at reflux for15 minutes and then allowed to cool to room temperature. The mixture wasfiltered and the off-white filter cake was washed with MTBE (2×3 mL) toprovide, after air drying at 100° C., the title compound as an off-whitefine powder.

Intermediate 2: Step a 6-(Trifluoromethyl)nicotinoyl chloride

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisenadaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple wasadded 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol),dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. Tothis solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and thereaction was allowed to stir at ambient temperature overnight. Thereaction was then filtered and the clear filtrate was concentrated invacuo to afford the title compound as a brownish semisolid.

Intermediate 2: Step bN-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide

To a 1 L 3-neck flask equipped with an overhead stirrer, Claisenadaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple wasadded 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235.2 mmol,Intermediate 2: step a), dichloromethane (493 mL), andN,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After themixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6mmol) was added such that the addition temperature did not exceed 16° C.After the addition, the reaction was allowed to warm to roomtemperature. The reaction was then transferred to a separatory funneland the organic layer was washed with saturated aqueous NaHCO₃ (2×100mL) followed by water (100 mL) and then dried over sodium sulfate, andfiltered. The solvent was then removed in vacuo to afford the titlecompound as a brownish oil.

Intermediate 2:Step c(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone

To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogenbubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96g, 297.9 mmol), followed by THF (537 mL). To this room temperaturesolution was added isopropylmagnesium chloride/lithium chloride complex[1.3 M in THF] (246.8 mL, 320.8 mmol) (addition temperature maintainedbetween 16.6 and 25° C.) to afford a milky suspension and the reactionwas stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. Tothis mixture was added a solution ofN-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14mmol, Intermediate 2: step b) in THF (268.3 mL) (addition temperaturebetween 5.3 and 5.6° C.) to afford an orange mixture. After addition,the reaction was warmed to room temperature over 2 hours. After stirringat room temperature for 18 hours, THF (200 mL) was added and thereaction was stirred for 2 hours. The reaction was then cooled to 4° C.with an ice bath and carefully quenched with 2 N aqueous HCl to pH=7,quenching temperature reached 12° C. The mixture was diluted with ethylacetate (500 mL), phases split and the organic layer was washed withbrine (2×200 mL), dried over sodium sulfate, filtered, and the solventwas removed. Hot ether was added and suspension was filtered to providethe title compound as a solid.

Intermediate 3 6-Bromo-2,4-dichloro-8-methyl-3-phenylquinoline

A mixture of 2-phenylmalonic acid (7.62 g, 42.3 mmol) and POCl₃ (32.8mL, 352 mmol) was stirred at reflux (130° C.) for 10 minutes, and theresulting homogeneous yellow solution was cooled in an ice bath.4-Bromo-2-methylaniline (6.56 g, 35.2 mmol) was added in one portion andthe mixture was refluxed for 2 hours. The dark solution was allowed tocool to room temperature and was diluted with DCM (70 mL) and ice (100mL), and stirred at room temperature for ˜5-10 minutes at which pointexothermic POCl₃ hydrolysis commenced (ice bath cooling), and was thenstirred at room temperature for another 30 minutes. The light yellowaqueous layer was extracted with DCM (1×30 mL), and the combined darkhomogeneous organic layers were dried (Na₂SO₄), filtered, andconcentrated with silica gel. The silica-adsorbed residue was dry loadflash chromatographed with a 20% DCM/heptane to 100% DCM gradient toprovide the title compound as an off-white solid.

Intermediate 4: 1-(4-Benzoylpiperidin-1-yl)ethanone

A mixture of phenyl(piperidin-4-yl)methanone hydrochloride (743 mg, 3.29mmol) in dichloromethane (13.2 mL) and triethylamine (1.10 mL, 7.90mmol) was treated with Ac₂O (0.373 mL, 3.95 mmol) dropwise over 1 minutein an ice bath under argon, and the resulting translucent mixture wasimmediately removed from the ice bath and stirred at room temperatureovernight. The reaction was then extracted with 1 M aqueous HCl (1×8 mL)and 1 M aqueous NaOH (1×8 mL), and the organic layer was dried (Na₂SO₄),filtered, and concentrated to provide the title compound as atranslucent beige oil that crystallized upon standing.

Intermediate 5: Step a 2-(3-(Trifluoromethyl)phenyl)acetyl chloride

To a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (4.78 g, 23.4mmol) in DCM (46 mL) was added oxalyl chloride (12.9 mL, 25.8 mmol). Onedrop of DMF was then added and the mixture was stirred for 1.5 hours atroom temperature. The mixture was concentrated to afford the titlecompound.

Intermediate 5: Step b Methyl5-bromo-2-(2-(3-(trifluoromethyl)phenyl)acetamido)benzoate

To a solution of 2-(3-(trifluoromethyl)phenyl)acetyl chloride (23.4 mmolassuming quantitative yield in previous step, Intermediate 5: step a) inDCM (50 mL) in an ice bath was added methyl 2-amino-5-bromobenzoate(4.90 g, 21.3 mmol) followed by triethylamine (6.51 mL, 46.8 mmol). Themixture was stirred at room temperature overnight. The reaction mixturewas washed with saturated aqueous NH₄Cl then water. The organic phasewas dried (Na₂SO₄), filtered, and concentrated and the residue waspurified by flash column chromatography (50-70% DCM-heptanes). Some ofthe title compound was obtained in pure form from the column, along withmixed fractions containing the title compound and the starting aniline.The mixed fractions were left to stand in DCM:heptanes (1:1) overnight,forming crystalline needles of the title compound, which were collectedby vacuum filtration and combined with clean fractions from the column.

Intermediate 5: Step c6-Bromo-4-hydroxy-3-(3-(trifluoromethyl)phenyl)quinolin-2(1H)-one

To a solution of methyl5-bromo-2-(2-(3-(trifluoromethyl)phenyl)acetamido)benzoate (3.86 g, 9.28mmol, Intermediate 5: step b) in THF (100 mL) at −78° C. was added KHMDS(0.5 M in toluene, 55.6 mL, 27.8 mmol) over 8 minutes. The resultinglight yellow solution was stirred at −78° C. for 5 minutes, then wastransferred to an ice bath and stirred for 1 hour 15 minutes. Themixture was diluted with water and extracted once with EtOAc. Theaqueous phase was acidified to pH 2 by addition of 1 N aqueous HClsolution. A white precipitate formed upon acidification and wascollected by vacuum filtration and air dried to afford the titlecompound as a white powder.

Intermediate 5: Step d6-Bromo-2,4-dichloro-3-(3-(trifluoromethyl)phenyl)quinoline

To a suspension of6-bromo-4-hydroxy-3-(3-(trifluoromethyl)phenyl)quinolin-2(1H)-one (3.17g, 8.25 mmol, Intermediate 5: step c) in acetonitrile (35 mL) was addedPOCl₃ (2.31 mL, 24.8 mmol). The resulting white suspension was heated atreflux under a drying tube for 2.5 hours. The mixture was allowed tocool to room temperature and stand for 2 hours. Precipitated solid wascollected by vacuum filtration to afford the title compound as a whitesolid.

Intermediate 5: Step e6-Bromo-4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline

To a suspension of6-bromo-2,4-dichloro-3-(3-(trifluoromethyl)phenyl)quinoline (1.48 g,3.52 mmol, Intermediate 5: step d) in toluene (15 mL) in a sealed tubewas added sodium methoxide (1.90 g, 35.2 mmol) in one portion. Theresulting white suspension was heated in a 100° C. oil bath for 24hours. An aqueous NaHCO₃ solution (10 wt. %, 27 mL) was added and themixture was stirred for a few minutes, and the phases were separated.The aqueous phase was extracted twice with EtOAc. The organic extractswere washed with saturated aqueous NaCl. The organic phase was dried(Na₂SO₄), filtered, and concentrated. The crude product was purified byflash column chromatography (silica gel, 15-30% DCM-heptanes) to affordthe title compound as a white powder.

Intermediate 6: Step a(1-Methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol

A solution of 1-methyl-1H-1,2,3-triazole (1.47 g, 17.7 mmol, PCT Int.Appl. 2008098104) in 20 mL THF was cooled to −40° C. in adry-ice/acetonitrile bath. n-Butyllithium (1.6 M in hexane, 10.2 mL,16.3 mmol) was added dropwise via syringe and the mixture was stirred at−40° C. for 30 minutes. A solution of1-methyl-1H-imidazole-5-carbaldehyde (1.50 g, 13.6 mmol) in 10 mL THFwas then added and the mixture was stirred for 5 minutes, then wastransferred to an ice/water bath. After 1 hour, the mixture was quenchedby addition of saturated aqueous NH₄Cl, diluted with water, andextracted twice with EtOAc. The aqueous phase, which contained the titlecompound, was then concentrated. The residue was purified by flashcolumn chromatography (silica gel, gradient 3-10% MeOH-DCM) to affordthe title compound as a light yellow foam.

Intermediate 6: Step b(1-Methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanone

A mixture of(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(1.90 g, 9.83 mmol, Intermediate 6: step a) and manganese dioxide (5.04g, 49.3 mmol) in 1,4-dioxane (100 mL) was stirred in a 100° C. oil bathunder argon for 2 hours. The mixture was allowed to cool to roomtemperature, then was filtered through a pad of Celite, rinsing withDCM. The filtrate was concentrated, yielding the title compound as abrown powder.

Intermediate 7: Step a Methyl 5-bromo-2-(2-phenylacetamido)benzoate

To a mixture of methyl 2-amino-5-bromobenzoate (9.00 g, 39.1 mmol) andEt₃N (7.6 mL, 54.8 mmol) in CH₂Cl₂ (90 mL) at 4° C. was added2-phenylacetyl chloride (7.26 g, 46.9 mmol) dropwise. After completionof the addition, the cooling bath was removed and the mixture wasstirred for 27 hours. TLC showed that some of the starting materialmethyl 2-amino-5-bromobenzoate still remained. More 2-phenylacetylchloride (1.88 g, 12.2 mmol) and Et₃N (2.2 mL, 15.9 mmol) were added,and the mixture was stirred overnight. K₂CO₃ (aqueous) was added, theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂. The combined organic layers were washed with water, dried(Na₂SO₄), filtered, and concentrated in vacuo. CH₃CN (100 mL) was added,and the precipitated solid was filtered, washed with Et₂O, and dried toafford the title compound. The filtrate was concentrated in vacuo, andthe solid was filtered, washed with Et₂O, and dried to provideadditional title compound.

Intermediate 7: Step b 6-Bromo-4-hydroxy-3-phenylquinolin-2(1H)-one

To a solution of methyl 5-bromo-2-(2-phenylacetamido)benzoate (7.71 g,22.1 mmol, Intermediate 7: step a) in THF (50 mL) at −78° C. was added1.0 M lithium bis(trimethylsilyl)amide in hexane (48.7 mL, 48.7 mmol)slowly, and the color changed from colorless to clear red. The mixture,at −78° C., was warmed to room temperature over 4 hours, during whichtime the color changed to cloudy yellow. The reaction was quenched withwater, and acidified with 37% HCl until pH ˜5. The precipitated solidwas filtered, washed with water and Et₂O, and air dried to provide thetitle compound. Another crop precipitated from the filtrate afterstanding overnight. The solid was collected by filtration, washing withwater and Et₂O, and air drying to afford additional title compound.

Intermediate 7: Step c 6-Bromo-2,4-dichloro-3-phenylquinoline

A solution of 6-bromo-4-hydroxy-3-phenylquinolin-2(1H)-one (8.50 g, 26.9mmol, Intermediate 7: step b) in phosphoryl trichloride (51 mL, 547mmol) was heated at 107° C. for 3.5 hours, and then cooled to roomtemperature. After evaporation of POCl₃ in vacuo, concentrated NH₄OH(aqueous) was added dropwise at 4° C. until pH 9. The precipitated solidwas filtered, washed with water, and dried at 50° C. under vacuumovernight to provide the title compound.

Intermediate 8: Step a 4-Chloro-N-methoxy-N-methylbenzamide

Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylaminehydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoylchloride (20 mL, 156 mmol) was then added and the mixture was stirred atroom temperature for 3 days. Solids were removed by vacuum filtration,washing with DCM. The filtrate was washed with 1 N aqueous HCl followedby water. The organic phase was dried (Na₂SO₄), filtered, andconcentrated, affording the crude title compound as a colorless liquidwhich was used without purification.

Intermediate 8: Step b(4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone

Ethyl magnesium bromide (3.0 M in diethyl ether, 21.5 mL, 64.4 mmol) wasadded via syringe over a few minutes to a clear colorless solution of5-bromo-1-methyl-1H-imidazole (10.4 g, 64.4 mmol) in THF (100 mL) undera nitrogen atmosphere in an ice bath. A white precipitate formed duringthe addition. The mixture was removed from the ice bath and was stirredfor 20 minutes, then was again cooled in an ice bath before addition of4-chloro-N-methoxy-N-methylbenzamide (10.7 g, 53.6 mmol, Intermediate 8:step a). The resulting white suspension was stirred overnight at roomtemperature. The reaction was quenched by addition of saturated aqueousNH₄Cl and diluted with water. The mixture was partially concentrated toremove THF and was diluted with DCM. The mixture was acidified to pH 1with 1 N aqueous HCl, then neutralized with saturated aqueous NaHCO₃.The phases were separated and the aqueous phase was further extractedwith DCM. The organic extracts were washed with water, then were dried(Na₂SO₄), filtered, and concentrated, affording a white solid. The crudeproduct was triturated with a mixture of EtOAc:heptanes (1:1, 150 mL).The precipitated solid was collected by vacuum filtration, washing withheptanes, to afford the title compound.

Intermediate 9: Step a Methyl5-bromo-2-(2-(pyridin-2-yl)acetamido)benzoate

Into a 250-mL round-bottom flask was placed a solution of methyl2-amino-5-bromobenzoate (5 g, 21.73 mmol), 2-(pyridin-2-yl)acetic acidhydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol) and DIEA (8.5g, 65.77 mmol) in N,N-dimethylformamide (100 mL). The resulting solutionwas stirred overnight at 20° C. The reaction was then quenched by theaddition of 100 mL of water. The resulting solution was extracted with3×100 mL of dichloromethane and the organic layers combined and driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was applied onto a silica gel column withdichloromethane/methanol (1:50) to afford the title compound as a redsolid.

Intermediate 9: Step b 6-Bromo-3-(pyridin-2-yl)quinoline-2,4(1H,3H)-dione

Into a 250-mL round-bottom flask was placed a solution of methyl5-bromo-2-[2-(pyridin-2-yl)acetamido]benzoate (3 g, 7.73 mmol,Intermediate 9: step a) and MeONa (11.7 mL, 31 mmol, 2.64 M in MeOH) intetrahydrofuran (30 mL). The resulting solution was stirred overnight at20° C. Then, the solvents were removed by a rotary evaporator and 50 mLwater was added to the residue. The pH of the resulting mixture wasadjusted to 7 with 1 M aqueous HCl. The solid was collected byfiltration and dried under vacuum to afford the title compound as awhite solid which was used in the next step without furtherpurification.

Intermediate 9: Step c 6-Bromo-2,4-dichloro-3-(pyridin-2-yl)quinoline

Into a 100-mL round-bottom flask was placed a solution of6-bromo-3-(pyridin-2-yl)quinoline-2,4(1H, 3H)-dione (2.54 g, 7.21 mmol,Intermediate 9: step b) in POCl₃ (50 mL). The resulting solution wasstirred for 3 hours at 120° C. The reaction was then quenched by theaddition of 50 mL of water. The resulting solution was extracted with3×50 mL of ethyl acetate and the organic layers combined and dried overanhydrous sodium sulfate, filtered and concentrated to afford the titlecompound as a white solid.

Intermediate 10: Step a Methyl5-bromo-2-(2-(pyridin-3-yl)acetamido)benzoate

Into a 250-mL round-bottom flask was placed a solution of methyl2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), 2-(pyridin-3-yl)aceticacid hydrochloride (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) andDIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). Theresulting solution was stirred overnight at 20° C. The reaction was thenquenched by the addition of 100 mL of water. The resulting solution wasextracted with 3×100 mL of dichloromethane and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2-1:1) to provide the title compound as ayellow solid.

Intermediate 10: Step b 6-Bromo-3-(pyridin-3-yl)quinoline-2,4(1H,3H)-dione

Into a 100-mL round-bottom flask, was placed a solution of methyl5-bromo-2-[2-(pyridin-3-yl)acetamido]benzoate (3 g, 7.73 mmol,Intermediate 10: step a) and MeONa (11.7 mL, 31 mmol, 2.64 M in MeOH) intetrahydrofuran (30 mL). The resulting solution was stirred overnight at20° C. The solids were collected by filtration and washed with water(3×5 mL). The solids were dried under vacuum to provide the titlecompound as a white solid.

Intermediate 10: Step c 6-Bromo-2,4-dichloro-3-(pyridin-3-yl)quinoline

Into a 100-mL round-bottom flask, was placed a solution of6-bromo-3-(pyridin-3-yl)quinoline-2,4(1H, 3H)-dione (700 mg, 1.99 mmol,Intermediate 10: step b) in phosphorus trichloride (20 mL). Theresulting solution was stirred for 3 hours at 120° C. The resultingmixture was concentrated under vacuum. The reaction was then quenched bythe addition of 20 mL of water. The resulting solution was extractedwith 3×20 mL of ethyl acetate and the organic layers combined and driedover anhydrous sodium sulfate, filtered and concentrated to afford thecrude title compound as a white solid.

Intermediate 11: Step a Methyl2-(2-(benzyloxy)acetamido)-5-bromobenzoate

To a solution of methyl-2-amino-5-bromobenzoate (15 g, 62.6 mmol) in DCM(241 mL) at 0° C. was added benzyloxyacetyl chloride (12.5 mL, 75.1mmol) followed by Et₃N (20 mL, 144 mmol) dropwise. The resulting whitesuspension was stirred at room temperature for 3 hours. The mixture wasthen washed with saturated aqueous NH₄Cl (200 mL) followed by water (200mL). The organics were dried (Na₂SO₄), filtered and concentrated todryness. The crude solid was triturated with MeOH (90 mL) and driedunder vacuum to afford the title compound as a white solid.

Intermediate 11: Step b3-(Benzyloxy)-6-bromo-4-hydroxyquinolin-2(1H)-one

To a solution of methyl 2-(2-(benzyloxy)acetamido)-5-bromobenzoate (15g, 39.7 mmol, Intermediate 11: step a) in THF (198 mL) was added KHMDS(1 M in THF, 119 mL, 119 mmol). The resulting solution was stirred atroom temperature for 40 minutes and then additional KHMDS (19.8 mL, 19.8mmol) was added and stirring continued at room temperature for 2 hours.The mixture was quenched with water (225 mL) and the layers wereseparated. The aqueous layer was acidified with 1 N aqueous HCl to pH2-3. Some of the title compound precipitated out of solution and wascollected by filtration. The aqueous was then extracted with EtOAc(3×200 mL). The organics were combined with the solid collectedpreviously and sonicated. The solution was dried (Na₂SO₄), filtered andconcentrated to dryness to provide the title compound as a yellow solid.

Intermediate 11: Step c 3-(Benzyloxy)-6-bromo-2,4-dichloroquinoline

To a suspension of 3-(benzyloxy)-6-bromo-4-hydroxyquinolin-2(1H)-one(12.4 g, 35.8 mmol, Intermediate 11: step b) in acetonitrile (119 mL)was added POCl₃ (10 mL, 107.5 mmol) followed by 2,6-lutidine (6.26 mL,53.7 mmol) dropwise. The suspension was heated to 100° C. for 4 hours,then the reaction was allowed to cool to room temperature. The solidswere filtered, rinsed with MeOH and dried under vacuum to afford thetitle compound as a tan solid.

Intermediate 11: Step d(3-(Benzyloxy)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

A solution of 3-(benzyloxy)-6-bromo-2,4-dichloroquinoline (2.57 g, 6.71mmol, Intermediate 11: step c) in THF (100 mL) was cooled to −78° C.,during which it became a white suspension. Then, nBuLi (1.6 M inhexanes, 5.87 mL, 9.39 mmol) was added dropwise and the resulting darkred solution was stirred for 10 minutes at −78° C. To this mixture wasadded a solution of(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(2.23 g, 8.72 mmol, Intermediate 2: step c) in THF (30 mL) over 4minutes and the resulting mixture stirred at −78° C. for 2 minutes. Thedry-ice/acetone bath was then replaced with an ice bath and the mixturewas stirred for an additional 45 minutes. The reaction was then quenchedwith water and extracted with EtOAc. The organics were combined, dried(MgSO₄), filtered and concentrated to dryness to afford the crudeproduct which was purified by FCC (4% MeOH/DCM) to provide the titlecompound.

Intermediate 11: Step e(3-(Benzyloxy)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

To a mixture of(3-(benzyloxy)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(2.46 g, 4.4 mmol, Intermediate 11: step d) in methanol (24.6 mL) wasadded NaOMe (0.5 M in MeOH, 8.8 mL, 4.4 mmol) and the resultingsuspension heated to 65° C. for 8 hours. The mixture was then cooled toroom temperature and concentrated to dryness. Water was added and themixture acidified with 2 N aqueous HCl to ˜pH 2. The aqueous was thenextracted with EtOAc. The organics were combined and washed with water,saturated aqueous NaHCO₃ and brine. The organics were then dried(MgSO₄), filtered and concentrated to dryness to afford the titlecompound which was used without further purification.

Intermediate 11: Step f4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-ol

To a solution of(3-(benzyloxy)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(2.56 g, 4.61 mmol, Intermediate 11: step e) in MeOH (97 mL) was added10% Pd/C (246 mg, 0.23 mmol). The reaction vessel was evacuated and thenplaced under an atmosphere of hydrogen for 1.5 hours. The mixture wasthen flushed with N₂ and filtered through a pad of Celite®. The filtratewas concentrated to dryness, then DCM was added and the solutionconcentrated to dryness. The resulting solid was dried in the oven. Thesolid was then purified by FCC (15% MeOH/DCM) to provide the titlecompound.

Intermediate 11: Step g4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yltrifluoromethanesulfonate

To a suspension of4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-ol(750 mg, 1.61 mmol, Intermediate 11: step f) in CH₂Cl₂ (15 mL) was addedpyridine (390 μL, 4.84 mmol) and the reaction became a solution. Thesolution was cooled to 0° C. and trifluoromethanesulfonic anhydride (683mg, 2.42 mmol) was added dropwise. The reaction was stirred at 0° C. for1 hour, then the ice bath was removed and stirring continued for anadditional hour. Trifluoromethanesulfonic anhydride (683 mg, 2.42 mmol)was then added and the mixture stirred at room temperature for 1 hour.The solution was poured into a mixture of 1 N aqueous HCl (20 mL) andice and then the aqueous was extracted with CH₂Cl₂. The organics werewashed with water followed by saturated aqueous NaHCO₃ and brine. Theaqueous layers were combined and back-extracted with EtOAc. The EtOAclayers were combined and washed with water followed by saturated aqueousNaHCO₃ and brine. The CH₂Cl₂ and EtOAc layers were combined, dried(MgSO₄), filtered and concentrated to dryness. The crude material waspurified by FCC (0-5% MeOH/CH₂Cl₂) to provide the title compound.

Intermediate 12: Step a(1-Methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

A solution of isopropylmagnesium chloride/lithium chloride complex (1.3M in THF, 19.5 mL, 25.35 mmol) was added dropwise by syringe to asolution of 5-bromo-1-methyl-1H-imidazole (4.12 g, 25.58 mmol) in dryTHF (130 mL) at 0° C. After 15 minutes, the Grignard solution was addedvia cannulation to a solution of picolinaldehyde (2.0 mL, 20.93 mmol) indry THF (55 mL) at 0° C. The reaction mixture was stirred for 5 minutesat 0° C., then warmed to room temperature for 1 hour. The reactionmixture was then cooled in an ice bath and quenched with saturatedaqueous ammonium chloride. The mixture was partitioned between brine andethyl acetate. The separated aqueous phase was further extracted withethyl acetate. The organic phase was dried (Na₂SO₄), filtered, andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 0-5% MeOH-DCM) to provide the title compoundas a white solid.

Intermediate 12: Step b(1-Methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone

A heterogenous mixture of(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol (1.41 g, 7.45 mmol,Intermediate 12: step a) and manganese dioxide (3.24 g, 37.27 mmol) in1,4-dioxane (52 mL) was stirred at 100° C. for 2 hours. The reactionmixture was then cooled to room temperature, filtered through Celite®,washed with DCM, and concentrated to provide the title compound as anoff-white solid.

Intermediate 13: Step a Diethyl 2-(4-(trifluoromethoxy)phenyl)malonate

CuI (0.26 g, 1.378 mmol), 2-picolinic acid (0.24 g, 1.969 mmol) andcesium carbonate (19.24 g, 59.061 mmol) were combined in a reactionvessel and the flask was evacuated and re-filled with argon (3 times).1,4-Dioxane was then added followed by diethylmalonate (6 mL, 39.374mmol) and 1-iodo-4-(trifluoromethoxy)benzene (3 mL, 19.687 mmol). Theresulting yellow suspension was stirred at room temperature for 48 hoursand quenched with saturated NH₄Cl. The mixture was extracted with EtOAc(2×). The combined organic extracts were dried over Na₂SO₄, filtered,and concentrated to provide the title compound.

Intermediate 13: Step b 2-(4-(Trifluoromethoxy)phenyl)malonic acid

A mixture of diethyl 2-(4-(trifluoromethoxy)phenyl)malonate (5.6 g,17.486 mmol, Intermediate 13: step a) and an aqueous 3 M NaOH solutionwas stirred in a 100° C. oil bath for 1 hour, cooled to roomtemperature, poured into ice water and acidified with 6 N aqueous HCl.The aqueous mixture was extracted with EtOAc. The EtOAc extract wasdried over Na₂SO₄, filtered, and evaporated in vacuo to provide thetitle compound.

Intermediate 13: Step c6-Bromo-2,4-dichloro-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline

A mixture of 2-(4-(trifluoromethoxy)phenyl)malonic acid (3.1 g, 11.74mmol, Intermediate 13: step b), 4-bromo-2-methylaniline (2.18 g, 11.74mmol) and POCl₃ (10 mL) was heated at 105° C. for 3 hours, cooled toroom temperature, concentrated under reduced pressure then slowly pouredinto ice water. A NH₄OH solution was added to a basic pH (pH 8-9). Theprecipitates were collected by filtration, rinsed with H₂O and driedunder high vacuum. The resulting tan solids were dissolved in DCM andchromatographed (heptane/DCM) to provide the title compound.

Intermediate 13: Step d6-Bromo-4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline

A mixture of6-bromo-2,4-dichloro-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline(1.97 g, 4.37 mmol, Intermediate 13: step c) and sodium methoxide (1.18g, 21.84 mmol) in toluene (20 mL) was heated in a sealed tube at 110° C.for 24 hours, cooled to room temperature, diluted with DCM, stirred atroom temperature for 30 minutes and filtered through Celite® rinsingseveral times with DCM. The solvents were removed under reduced pressureand the off-white solid product precipitated from MeOH, filtered anddried to provide the title compound.

Intermediate 14: Step a tert-Butyl4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate

A solution of isopropylmagnesium chloride (2.0 M in THF, 40.3 mL, 80.6mmol) was added dropwise by syringe to a solution of5-bromo-2-(trifluoromethyl)pyridine (19.5 g, 86.3 mmol) in dry THF (12mL) at 2° C. After 30 minutes, tert-butyl4-formylpiperidine-1-carboxylate (12.3 g, 57.3 mmol) was added to theGrignard solution at 2° C. as a solid. The reaction mixture was warmedto 10° C. over 1.5 hours after which it was quenched with saturatedaqueous ammonium chloride solution. The mixture was partitioned betweenwater and ethyl acetate. The separated aqueous phase was furtherextracted with ethyl acetate and washed with saturated aqueous NaClsolution. The organic phase was dried (MgSO₄), filtered, andconcentrated and used crude in the next step.

Intermediate 14: Step b tert-Butyl4-(6-(trifluoromethyl)nicotinoyl)piperidine-1-carboxylate

Dess-Martin periodinane reagent (30.0 g, 70.8 mmol) was added to asolution of tert-butyl4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate(Intermediate 14: step a, 17.8 g, 49.5 mmol) in DCM at room temperatureand the mixture was stirred for 2 hours. The reaction mixture wasdiluted with DCM and washed with saturated aqueous solution of NaHCO₃.The organic phase was dried (MgSO₄), filtered, and concentrated. Thecrude product was purified by flash column chromatography (silica gel,0-60% EtOAc-hexanes) to provide the title compound that was 90% pure byNMR and was carried on to the next step.

Intermediate 14: Step cPiperidin-4-yl(6-(trifluoromethyl)pyridin-3-yl)methanone

TFA (34.4 mL, 449.3 mmol) was added to a solution of tert-butyl4-(6-(trifluoromethyl)nicotinoyl)piperidine-1-carboxylate (Intermediate14: step b, 16.1 g, 44.9 mmol) in DCM (450 mL) and the resultingsolution was stirred at room temperature for 3 hours. The mixture wasconcentrated to remove most of the TFA on the rotary evaporator and amixture of EtOAc/hexanes was added. The white solid that precipitatedwas filtered and dried and used in the next step.

Intermediate 14: Step d1-(4-(6-(Trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone

TEA (32.1 mL, 230.9 mmol) was added to a solution ofpiperidin-4-yl(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate14: step c, 14.3 g, 38.5 mmol) in DCM (427 mL) followed by aceticanhydride (5.28 mL, 55.8 mmol). The mixture was stirred for 2 hours andtransferred to a separatory funnel and washed with 100 mL of aqueous 2 MNaH₂PO₄ solution. The organic layer was dried (MgSO₄), filtered andconcentrated. The crude product was purified by flash columnchromatography (silica gel, 0-3% MeOH-DCM) to provide the titlecompound.

Intermediate 15: Step a N-Methoxy-N-methylpyrimidine-2-carboxamide

Sodium pyrimidine-2-carboxylate (4.00 g, 27.4 mmol), imidazolehydrochloride (3.15 g, 30.1 mmol), and 1-carbonyldiimidazole (5.26 g,31.5 mmol) were slurried in acetonitrile (30 mL) at room temperatureunder an N₂ atmosphere. The mixture was then warmed to 52° C. over 30minutes. Evolution of carbon dioxide was seen when reaction mixturereached approximately 50° C. The mixture was then stirred at 52° C. forapproximately 2 hours. The reaction was then cooled to room temperature,then N,O-dimethylhydroxylamine hydrochloride (3.54 g, 35.6 mmol) wasthen added slowly, portion wise over approximately 15 minutes and a mildexotherm was seen after each addition. The contents were stirred at roomtemperature overnight. To the reaction mixture was then added deionizedwater (25 mL) and dichloromethane (25 mL). 6 M Aqueous hydrochloric acidwas added dropwise to acidify the aqueous layer to approximately pH 1.The organic phase was then separated and the aqueous phase was extractedtwice with dichloromethane. The combined organics were washed with 2 Maqueous hydrochloric acid, separated, then the acidic layer wasextracted twice with dichloromethane. The combined organic phases werewashed with a saturated, aqueous NaHCO₃ solution, then dried over MgSO₄,filtered and the solvent was removed by distillation under reducedpressure to provide the title compound.

Intermediate 15: Step b(1-Methyl-1H-imidazol-5-yl)(pyrimidin-2-yl)methanone

5-Bromo-1-methyl-1H-imidazole (6.66 g, 41.4 mmol) was added to a roundbottom flask followed by tetrahydrofuran (150 mL) under an N₂atmosphere. The contents were cooled to 0° C. in an ice water bath.EtMgBr (3.0 M solution in THF, 13.3 mL, 39.8 mmol) was added slowly viasyringe over approximately 5 minutes, then the ice bath was removed andcontents allowed to warm and stirred at room temperature forapproximately 30 minutes. The vessel was then re-cooled to 0° C. and asolution of N-methoxy-N-methylpyrimidine-2-carboxamide (3.09 g, 15.9mmol, Intermediate 15: step a) in THF (20 mL) was cannulated into thereaction vessel. The contents were allowed to stir at 0° C., then slowlywarmed to room temperature, then heated to 40° C. in an oil bath andheated with stirring at that temperature for approximately 36 hours. Thecontents were then cooled to 0° C., quenched with a saturated aqueousNH₄Cl solution, diluted with ethyl acetate and transferred to aseparatory funnel. The aqueous layer was separated, extracted twice withEtOAc, then the combined organic phases were dried over MgSO₄, filtered,then distilled under reduced pressure to afford an amber oil. The crudeproduct was purified by flash column chromatography (silica gel, 0-10%DCM/(10% of a 2 M NH₃ MeOH in DCM)) to provide the title compound.

Intermediate 16: Step a(2,4-Dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

1-Methyl-1H-1,2,3-triazole was prepared according to the literaturereference WO2008/98104. To a 2 L flask containing1-methyl-1H-1,2,3-triazole (9 g, 108.3 mmol) was added THF (1500 mL) andthe solution was cooled to −40° C. To this colorless homogeneoussolution was added n-butyllithium (2.5 M in hexanes, 45 mL, 112.5 mmol)dropwise which immediately afforded a dark brown viscous mixture. Themixture was kept between −10 to −20° C. for 60 minutes, then a THFsolution of 2,4-dimethylthiazole-5-carbaldehyde (17.2 g, 121.8 mmol in200 mL THF) was introduced via cannula. Once the aldehyde was added thereaction was allowed to warm to room temperature. After 3 hours, thereaction was quenched by pouring it into a saturated solution of aqueousNH₄Cl. The aqueous portion was extracted with EtOAc in portions, 7×400mL. The combined organics were washed with brine, dried over MgSO₄,filtered and concentrated to afford a brown oil. Chromatography onsilica gel (10% acetone-DCM increasing to 50% acetone and increasing to10% MeOH-DCM) provided the title compound as an amber solid.

Intermediate 16: Step b(2,4-Dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone

To a 500 mL flask containing(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (10.5g, 46.8 mmol, Intermediate 16: step a) was added 1,4-dioxane (400 mL)and the contents were warmed to form a homogeneous solution. ActivatedMnO₂ (18 g, 207 mmol) was added and the dark brownish mixture was heatedto reflux in an aluminum heating mantle under an atmosphere of N₂. After1.5 hours, the contents were filtered while still hot through Celite®and rinsed with warm THF. The resulting light orange solution wasconcentrated and passed through a silica gel column (25% acetone-DCM) toprovide the title compound as a light orange solid.

Intermediate 17: Step a N-Methoxy-N,2,4-trimethylthiazole-5-carboxamide

To a flask containing 2,4-dimethylthiazole-5-carboxylic acid (2.5 g,15.9 mmol) was added DCM (75 mL) to give a suspension. DMF (3 mL) wasadded which resulted in a homogeneous solution. Then,carbonyldiimidazole (2.84 g, 17.5 mmol) was introduced and the mixturewas stirred at room temperature for 2 hours. N,O-dimethylhydroxylamineHCl (1.9 g, 19.9 mmol) was then added and the mixture was stirred atroom temperature for 18 hours, at which time the reaction mixture wasdiluted with water and 1 N aqueous NaOH and the aqueous portion wasextracted with DCM (4×50 mL). The combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated. Chromatography onsilica gel (10% EtOAc-DCM increasing to 40% EtOAc) provided the titlecompound as a colorless oil.

Intermediate 17: Step b(2,4-Dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanone

To a flask containing 5-bromo-1-methyl-1H-imidazole (390 mg, 2.42 mmol)was added THF (8 mL) and the solution was cooled to 0° C. To thissolution was added isopropylmagnesium chloride-LiCl complex (1.3 M inTHF, 2.5 mL, 3.25 mmol) which resulted in a white suspension. Thereaction mixture was stirred in a 0° C. bath for 30 minutes, then a THF(2 mL) solution of N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (550mg, 2.75 mmol, Intermediate 17: step a) was introduced. The reactionmixture was stirred at 50° C. for 18 hours, cooled to room temperatureand quenched with aqueous NH₄Cl solution. The aqueous portion wasextracted with DCM (4×50 mL) and the combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated. Chromatography onsilica gel (25% EtOAc-DCM increasing to 5% MeOH-DCM) afforded the titlecompound as an amber solid.

Intermediate 18: Step a(2,4-Dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol

To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (4 g, 11.33mmol, Intermediate 7: step c) was added THF (200 mL) to give ahomogeneous clear solution. The solution was cooled in a dry-ice bathand n-BuLi (2.5 M in hexanes, 4.25 mL, 10.63 mmol) was added whichresulted in an immediate reddish-brownish mixture. After 2 minutes, aTHF solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (1.75 g, 14.1mmol in 10 mL THF) was added and the reaction mixture became a lightyellow color. The −78° C. bath was replaced with a 0° C. ice-bath andafter 40 minutes, the reaction mixture was quenched with aqueous NH₄Clsolution and the aqueous portion was extracted with EtOAc (4×100 mL).The combined organics were washed with brine, dried over MgSO₄, filteredand concentrated. The resulting solid was triturated with Et₂O toprovide the title compound as an off white powder.

Intermediate 18: Step b(2,4-Dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol(520 mg, 1.31 mmol, Intermediate 18: step a) was added 1,4-dioxane (12mL) followed by manganese dioxide (475 mg, 5.46 mmol). The mixture washeated to reflux for 3.25 hours and then the contents were filteredthrough a Celite® pad, while still warm, and the Celite® pad was rinsedwith warm THF. The effluent was concentrated under reduced pressure toprovide the title compound as an off white foam.

Intermediate 19: Step a6-Bromo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol

A mixture of 2-amino-5-bromobenzoic acid (3.01 g, 13.9 mmol),1,1,1-trifluoro-3-phenylpropan-2-one (3.11 g, 16.5 mmol), and Eaton'sreagent (9.3 mL) in a sealed tube was heated at 100° C. for 4 hours. Thereaction mixture was then allowed to cool to room temperature, water wasadded slowly, and the mixture was stirred vigorously for about 15minutes. The precipitated solid was collected by filtration, washed withwater, and dried to provide the title compound.

Intermediate 19: Step b6-Bromo-4-chloro-3-phenyl-2-(trifluoromethyl)quinoline

A solution of 6-bromo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (8.29 g,22.5 mmol, Intermediate 19: step a) in phosphoryl trichloride (25 mL,269 mmol) was heated at 110° C. for 2 hours, and concentrated in vacuo.Dichloromethane and ice-water were added, and the mixture was basifiedat 4° C. with concentrated NH₄OH until pH˜10. The organic layer wasseparated and the aqueous layer was extracted with CH₂Cl₂. The combinedorganic phases were dried (Na₂SO₄), concentrated, and purified by flashcolumn chromatography (120 g silica gel column, 2-9% EtOAc in heptanes)to afford the title compound as a light yellow solid.

Intermediate 20: Step a 6-Iodo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol

A mixture of 2-amino-5-iodobenzoic acid (5.20 g, 19.8 mmol),1,1,1-trifluoro-3-phenylpropan-2-one (3.95 g, 21.0 mmol), and Eaton'sreagent (12 mL) in a sealed tube was heated at 100° C. for 2 hours. More1,1,1-trifluoro-3-phenylpropan-2-one (1.60 g, 8.50 mmol) was added andthe mixture was heated for another 2 hours. The reaction was then cooledto room temperature, ice water was added, and the mixture was stirredvigorously for about 20 minutes. 50% Aqueous NaOH and concentrated NH₄OHsolutions were added until pH 9. The resulting dark brown gummy materialthat formed was diluted with DCM which resulted in a solid precipitatethat was collected by filtration. The solids were washed with water andEt₂O and air dried to provide the title compound.

Intermediate 20: Step b4-Chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline

A solution of 6-iodo-3-phenyl-2-(trifluoromethyl)quinolin-4-ol (1.54 g,3.71 mmol, Intermediate 20: step a) in phosphoryl trichloride (5 mL,53.8 mmol) was heated at 110° C. for 1 hour 45 minutes, and then cooledto room temperature. Ice-water was added, and the mixture was basifiedat 4° C. with 50% aqueous NaOH and concentrated NH₄OH until pH 9. Theprecipitated solid was filtered, washed with water and Et₂O, and driedto provide the title compound. The filtrate was separated and theaqueous layer was extracted with CH₂Cl₂. The combined organic phaseswere dried (Na₂SO₄), concentrated, and purified by flash columnchromatography (80 g silica gel column, 0-5% EtOAc in heptanes),affording a mixture of the title compound and des-iodo by-product,4-chloro-3-phenyl-2-(trifluoromethyl)quinoline, in about 8:1 ratio as athick oil, which solidified over night.

Intermediate 21 tert-Butyl 4-nicotinoylpiperidine-1-carboxylate

A mixture of piperidin-4-yl(pyridin-3-yl)methanone hydrochloride (397mg, 1.75 mmol), di-tert-butyl dicarbonate (710 mg, 3.25 mmol),N,N-dimethylpyridin-4-amine (28 mg, 0.23 mmol) and Et₃N (1.2 mL, 8.6mmol) in THF (15 mL) and CH₂Cl₂ (5 mL) was stirred for 3 days and thenconcentrated. The residue was purified by flash column chromatography(40 g silica gel column, 50-70% EtOAc in heptane) to provide the titlecompound as a clear oil.

Intermediate 22: Step a(3-Chlorophenyl)(6-(trifluoromethyl)pyridin-3-yl)methanone

To a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide(1.23 g, 5.25 mmol, Intermediate 2: step b) in THF (12 mL) at 4° C. wasadded 0.5 M (3-chlorophenyl)magnesium bromide in THF (12.7 mL, 6.35mmol). The mixture was stirred at 4° C. to room temperature overnight,and quenched with NH₄Cl (aqueous). The organic layer was separated, andthe aqueous layer was extracted with CH₂Cl₂. The combined organic phaseswere dried (Na₂SO₄), filtered, concentrated, and purified by flashcolumn chromatography (40 g silica gel column, 0-70% EtOAc in heptanes)to provide the title compound as an oil, which solidified upon standing.

Intermediate 22: Step b(3-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

To a solution of 6-bromo-2,4-dichloro-3-phenylquinoline (422 mg, 1.20mmol, Intermediate 7: step c) and(3-chlorophenyl)(6-(trifluoromethyl)pyridin-3-yl)methanone (340 mg, 1.19mmol, Intermediate 22: step a) in THF (8 mL) at −78° C. was added 1.6 Mn-BuLi in hexane (1.14 mL, 1.82 mmol). The mixture was stirred at −78°C. to 10° C. for 2 hours and then quenched with NH₄Cl (aqueous). Theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂. The combined organic phases were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography (24 g silicagel column, 30-40% EtOAc in heptane) to provide the title compound as awhite solid.

Intermediate 23: Step aN-Methoxy-N-methyl-2-(trifluoromethyl)isonicotinamide

To a suspension of 2-(trifluoromethyl)isonicotinic acid (1.03 g, 5.39mmol), N,O-dimethylhydroxylamine hydrochloride (0.800 g, 8.20 mmol) andN(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride(EDCI, 1.35 g, 7.04 mmol) in CH₂Cl₂ (30 mL) was added Et₃N (1.90 mL,13.7 mmol), and the mixture immediately turned clear. After stirring atroom temperature overnight, NH₄Cl (aqueous) was added. The mixture wasstirred vigorously for a while, and white solid was then filtered off.The organic layer was separated, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic phases were washed with brine, and theaqueous layer was back extracted with CH₂Cl₂. The organic phases werecombined, dried (Na₂SO₄), filtered, concentrated, and purified by flashcolumn chromatography (40 g silica gel column, 40-70% EtOAc in heptanes)to afford the title compound as a clear oil.

Intermediate 23: Step b(3-Chlorophenyl)(2-(trifluoromethyl)pyridin-4-yl)methanone

The title compound was prepared usingN-methoxy-N-methyl-2-(trifluoromethyl)isonicotinamide (Intermediate 23:step a) in place of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide(Intermediate 2: step b) according to the procedure described inIntermediate 22: step a.

Intermediate 24(3-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol

The title compound was prepared using(3-chlorophenyl)(pyridin-3-yl)methanone in place of(3-chlorophenyl)(6-(trifluoromethyl)pyridin-3-yl)methanone (Intermediate22: step a) according to the procedure described in Intermediate 22:step b.

Intermediate 25: Step a N-Methoxy-N-methylisonicotinamide

A suspension of 4-picolinic acid (3.00 g, 24.4 mmol) and1,1-carbonyldiimidazole (4.74 g, 29.2 mmol) in CH₂Cl₂ (35 mL) wasstirred for ˜40 minutes, at which time it became a clear solution. Afterthe addition of N,O-dimethylhydroxylamine hydrochloride (2.85 g, 29.2mmol), the mixture was stirred at room temperature for 22 hours. Waterwas added, the organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withwater once, and the aqueous layer was back extracted with CH₂Cl₂. Theorganic phases were combined, dried (Na₂SO₄), filtered, concentrated,and purified by flash column chromatography (80 g silica gel column,100% EtOAc) to provide the title compound as a clear oil.

Intermediate 25: Step b(1-Methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanone

To a heat-gun dried flask containing 1-methyl-1H-imidazole (2.2 mL, 27.7mmol) and THF (13 mL) at −78° C. was added 1.6 M n-BuLi in hexane (18.5mL, 29.6 mmol). After stirring at −78° C. for 40 minutes, neatchlorotriethylsilane (4.9 mL, 29.2 mmol) was introduced slowly. Themixture was stirred at −78° C. for 1 hour. 1.6 M n-BuLi in hexane (18mL, 28.8 mmol) was added, and stirring became very difficult. Thecooling bath was removed, and stirring was continued for a while beforethe temperature reached around 10° C. The mixture was re-cooled to −78°C., a solution of N-methoxy-N-methylisonicotinamide (3.82 g, 23.0 mmol,Intermediate 25: step a) in THF (28 mL) was added via cannula, andstirring stopped. The cooling bath was removed, and the stirring wascontinued for 40 minutes before room temperature was reached. Thereaction was quenched with a few drops of MeOH. Brine was added, theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂. The combined organic phases were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography (silica gel,50-100% EtOAc in heptane, then 5-10% MeOH in CH₂Cl₂) to afford the titlecompound as an off-white solid.

Intermediate 25: Step c(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA

To a solution of 6-bromo-2,4-dichloro-3-phenylquinoline (1.46 g, 4.14mmol, Intermediate 7: step c) and(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanone (778 mg, 4.16 mmol,Intermediate 25: step b) in THF (65 mL) at −78° C. was added 1.6 Mn-BuLi in hexane (3.90 mL, 6.24 mmol). After stirring at −78° C. to roomtemperature overnight, the mixture was quenched with NH₄Cl (aqueous).The organic layer was separated, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic phases were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography (80 g silicagel column, 100% EtOAc, then 5-10% MeOH in CH₂Cl₂) and then reversephase HPLC (water/acetonitrile/0.1% TFA) to afford the title compound.

Intermediate 26(4-Butyl-2-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA

The title compound was isolated as a by-product from the reaction thatformed(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol(Intermediate 25: step c).

Intermediate 27(2,4-Dichloro-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol.TFA

The title compound was prepared usingpyridin-2-yl(pyridin-4-yl)methanone in place of(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanone (Intermediate 25:step b) according to the procedure described in Intermediate 25: step c.

Intermediate 28: Step a 2-Fluoro-N-methoxy-N-methylisonicotinamide

The title compound was prepared using 2-fluoroisonicotinic acid in placeof 4-picolinic acid according to the procedure described in Intermediate25: step a.

Intermediate 28: Step b(2-Fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanone

The title compound was prepared using2-fluoro-N-methoxy-N-methylisonicotinamide (Intermediate 28: step a) inplace of N-methoxy-N-methylisonicotinamide (Intermediate 25: step a)according to the procedure described in Intermediate 25: step b.

Intermediate 29 tert-Butyl4-((2,4-dichloro-3-phenylquinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate

To a solution of 6-bromo-2,4-dichloro-3-phenylquinoline (174 mg, 0.490mmol, Intermediate 7: step c) and tert-butyl4-nicotinoylpiperidine-1-carboxylate (143 mg, 0.490 mmol, Intermediate21) in THF (5 mL) at −78° C. was added 1.6 M n-BuLi in hexane (0.47 mL,0.75 mmol). The mixture was stirred at −78° C. to 0° C. for 3 hours andquenched with NH₄Cl (aqueous). The organic layer was separated, and theaqueous layer was extracted with CH₂Cl₂. The combined organic phaseswere dried (Na₂SO₄), filtered, concentrated, and purified by flashcolumn chromatography (40 g silica gel column, 50-70% EtOAc in heptane)to provide the title compound as a solid.

Intermediate 30 (4-Chlorophenyl)(2,4-dimethylthiazol-5-yl)methanone

To a flask containing N-methoxy-N,2,4-trimethylthiazole-5-carboxamide(510 mg, 2.55 mmol, Intermediate 17: step a) was added THF (18 mL) andthe solution was cooled to 0° C. To this solution was added(4-chlorophenyl)magnesium chloride (1 M in diethylether, 3.3 mL, 3.3mmol). A homogeneous yellow mixture resulted and was allowed to warm toroom temperature over 15 minutes. After 2 hours, the reaction mixturewas quenched with aqueous NH₄Cl solution and the aqueous portion wasextracted with EtOAc (4×50 mL). The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated to dryness.Chromatography on silica gel (100% DCM increasing to 10% EtOAc-DCM)provided the title compound as a white solid.

Intermediate 31: Step a N-(4-Bromophenyl)-2-phenylacetamide

Into a 250-mL round-bottom flask were placed a solution of4-bromoaniline (17.1 g, 99.42 mmol) and triethylamine (30 g, 297 mmol)in dichloromethane (100 mL). Then, 2-phenylacetyl chloride (18.6 g, 120mmol) was added dropwise with stirring, and the resulting solution wasstirred at room temperature for 6 hours. The solids were filtered out,and the filtrate was concentrated under vacuum. The crude product waspurified by re-crystallization from ethyl acetate to provide the titlecompound as a white solid.

Intermediate 31: Step b 6-Bromo-2-chloro-3-phenylquinoline

Into a 50-mL round-bottom flask were placed N,N-dimethylformamide (2.15g, 29.45 mmol) and phosphoryl trichloride (20.3 g, 132.7 mmol) and themixture was cooled to 0° C. Then, N-(4-bromophenyl)-2-phenylacetamide(5.7 g, 17.87 mmol, Intermediate 23: step a) was added in portions. Theresulting solution was heated at 80° C. for 5 hours, then concentratedunder vacuum, followed by dilution with 50 mL of H₂O, and thenextraction with 3×50 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by FCC (1:10 EtOAc/petroleum ether) toafford the title compound as a yellow solid.

Intermediate 32: Step a Methyl5-bromo-2-(2-(2-chlorophenyl)acetamido)benzoate

The title compound was prepared using 2-chlorophenylacetyl chloride inplace of 2-phenylacetyl chloride using the procedure described forIntermediate 7: step a.

Intermediate 32: Step b6-Bromo-3-(2-chlorophenyl)-4-hydroxyquinolin-2(1H)-one

The title compound was prepared using methyl5-bromo-2-(2-(2-chlorophenyl)acetamido)benzoate (Intermediate 32: stepa) in place of 5-bromo-2-(2-phenylacetamido)benzoate using the proceduredescribed for Intermediate 7: step b.

Intermediate 32: Step c 6-Bromo-2,4-dichloro-3-(2-chlorophenyl)quinoline

The title compound was prepared using6-bromo-3-(2-chlorophenyl)-4-hydroxyquinolin-2(1H)-one (Intermediate 32:step b) in place of 6-bromo-4-hydroxy-3-phenylquinolin-2(1H)-one usingthe procedure described for Intermediate 7: step c.

Example 1a1-(4-((4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone

n-Butyllithium (1.6 M in hexane, 0.585 mL, 0.937 mmol) was added over 1minute to a solution of6-bromo-4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline (409.8mg, 0.984 mmol, Intermediate 5: step e) in THF (3 mL) at −78° C. After 1minute, a solution of1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (231.4mg, 0.984 mmol, Intermediate 1: step c) in THF (5 mL) was added viacannula. The mixture was stirred at −78° C. for 10 minutes, then wastransferred to an ice bath and stirred for 45 minutes. The reactionmixture was quenched by addition of saturated aqueous NH₄Cl, dilutedwith water, and extracted with EtOAc (3×). The organic phase was dried(Na₂SO₄), filtered, and concentrated to dryness. The residue waspurified by flash column chromatography (silica gel, 0-8% MeOH-DCM) toafford the target compound as a white solid. MS m/e 573.3 [M+H]⁺.

1-(4-((4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanonewas purified by chiral HPLC (Chiralcel OD-H, EtOH) to give 2enantiomers. Example 1b: (first enantiomer to elute off chiral column)¹H NMR (400 MHz, CDCl₃, 1.2:1 mixture of rotamers, minor rotamer peaksmarked *) δ 8.21 (s, 1H), 8.16* (br. s., 1H), 7.85* (d, J=2.53 Hz, 1H),7.83 (d, J=2.53 Hz, 1H), 7.72* (s, 1H), 7.70 (s, 1H), 7.59-7.66 (m, 4H),7.54-7.58 (m, 2H), 7.41-7.51 (m, 2H), 7.34 (s, 2H), 7.23 (s, 2H), 4.78(d, J=12.63 Hz, 1H), 4.61* (d, J=12.63 Hz, 1H), 4.01 (s, 6H), 3.95 (d,J=13.14 Hz, 1H), 3.76* (d, J=11.12 Hz, 1H), 3.28 (s, 3H), 3.27* (s, 3H),3.11-3.24* (m, 1H), 2.94-3.04 (m, 1H), 2.56-2.70 (m, 3H), 2.40-2.56 (m,3H), 2.25-2.38 (m, 2H), 2.05 (s, 3H)*, 2.03 (s, 3H), 1.13-1.44 (m, 6H);MS m/e 573.2 [M+H]⁺ and Example 1c: (second enantiomer to elute offchiral column) ¹H NMR (400 MHz, CDCl₃, 1.2:1 mixture of rotamers, minorrotamer peaks marked *) δ 8.21 (s, 1H), 8.16* (br. s., 1H), 7.84* (d,J=3.03 Hz, 1H), 7.82 (d, J=2.53 Hz, 1H), 7.71* (s, 1H), 7.69 (s, 1H),7.58-7.65 (m, 4H), 7.52-7.58 (m, 2H), 7.40-7.51 (m, 2H), 7.29-7.35 (m,2H), 7.22 (s, 2H), 4.77 (d, J=13.1 Hz, 1H), 4.60 (d, J=13.6 Hz, 1H),4.00 (s, 6H), 3.93 (d, J=12.63 Hz, 1H), 3.74* (d, J=13.14 Hz, 1H), 3.27(s, 3H), 3.26* (s, 3H), 3.12-3.22 (m, 1H), 2.92-3.05 (m, 1H), 2.80 (s,1H), 2.57-2.74 (m, 2H), 2.39-2.55 (m, 3H), 2.22-2.39 (m, 2H), 2.04* (s,3H), 2.02 (s, 3H), 1.12-1.46 (m, 6H); MS m/e 573.2 [M+H]⁺.

Example 2a6-((1-Acetylpiperidin-4-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrile

A round bottom flask was charged with1-(4-((4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone(158 mg, 0.276 mmol, Example 1a), Zn(CN)₂ (58.3 mg, 0.496 mmol),Pd₂(dba)₃ (37.9 mg, 0.041 mmol), zinc nanopowder (5.4 mg, 0.083 mmol),and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos, 27.1 mg, 0.055 mmol). The flask was evacuated and re-filledwith argon (three cycles). Dimethylacetamide (1.4 mL, sparged with argonfor 30 minutes) was then added and the mixture was heated at 120° C. for4 hours. The mixture was cooled to room temperature and was filteredthrough Celite®, washing with EtOAc. The filtrate was washedsequentially with 2 M aqueous NH₄OH, water, and saturated aqueous NaCl.The organic phase was dried (Na₂SO₄), filtered, and concentrated todryness. The residue was purified by flash column chromatography (silicagel, 1-8% MeOH-DCM) to afford the title compound. MS m/e 564.3 [M+H]⁺.

6-((1-Acetylpiperidin-4-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrilewas purified by chiral HPLC (Chiralcel OD-H, EtOH) to give 2enantiomers. Example 2b: (first enantiomer to elute off chiral column)¹H NMR (400 MHz, CDCl₃, 1.1:1 mixture of rotamers, minor rotamer peaksmarked *) δ 8.28 (s, 1H), 8.24* (s, 1H), 7.84-7.91 (m, 2H), 7.71-7.84(m, 6H), 7.63-7.71 (m, 2H), 7.43-7.50 (m, 2H), 7.29-7.33 (m, 2H), 7.21(s, 2H), 4.76 (d, J=14.65 Hz, 1H), 4.59* (d, J=11.12 Hz, 1H), 4.06* (s,6H), 3.94 (d, J=12.63 Hz, 1H), 3.68-3.80 (m, 1H), 3.29 (s, 3H), 3.27*(s, 3H), 3.22 (s, 1H), 3.13-3.22* (m, 1H), 3.10* (s, 1H), 2.93-3.04 (m,1H), 2.58-2.71 (m, 1H), 2.23-2.57 (m, 5H), 2.04 (s, 3H), 2.03 (s, 3H),1.12-1.47 (m, 6H); MS m/e 564.2 [M+H]⁺ and Example 2c: (secondenantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃, 1.1:1mixture of rotamers, minor rotamer peaks marked *) δ 8.28 (s, 1H), 8.24*(s, 1H), 7.88-7.90* (m, 1H), 7.85-7.87 (m, 1H), 7.71-7.83 (m, 6H),7.64-7.71 (m, 2H), 7.42-7.50 (m, 2H), 7.31-7.34 (m, 2H), 7.22 (s, 2H),4.77 (d, J=13.14 Hz, 1H), 4.60* (d, J=14.15 Hz, 1H), 4.07 (s, 6H), 3.94*(d, J=14.15 Hz, 1H), 3.68-3.80 (m, 1H), 3.28 (s, 3H), 3.27* (s, 3H),3.13-3.23 (m, 1H), 2.96-3.05* (m, 1H), 2.95 (s, 1H), 2.84* (s, 1H),2.58-2.70 (m, 1H), 2.22-2.57 (m, 5H), 2.05* (s, 3H), 2.03 (s, 3H),1.17-1.45 (m, 6H); MS m/e 564.2 [M+H]⁺.

Example 3a(4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol

n-Butyllithium (1.6 M in hexane, 0.547 mL, 0.876 mmol) was added over 1minute to a solution of6-bromo-4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline (383mg, 0.919 mmol, Intermediate 5: step e) in THF (3 mL) at −78° C. After 5minutes, a solution of(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanone(176 mg, 0.919 mmol, Intermediate 6, step b) in THF (15 mL) was addedvia cannula. The mixture was stirred at −78° C. for 5 minutes, then wastransferred to an ice bath and stirred for 30 minutes. The reactionmixture was quenched by addition of saturated aqueous NH₄Cl, dilutedwith water, and extracted with EtOAc (3×). The organic phase was washedtwice with water. The organic phase was dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash column chromatography(silica gel, 1-7% MeOH-DCM) to afford the target compound as a whitesolid. MS m/e 529.2 [M+H]⁺.

(4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanolwas purified by chiral SFC (Chiralpack IC, 75% CO₂, 25% (0.2%isopropylamine-2-propanol)) to give 2 enantiomers. The enantiomers werethen further purified individually on plug silica gel columns (0-5%MeOH-DCM). Example 3b: (first enantiomer to elute off chiral column) ¹HNMR (400 MHz, CDCl₃) δ 8.30 (br. s., 1H), 7.82-8.09 (br. s., 1H), 7.78(d, J=9.1 Hz, 1H), 7.70-7.75 (m, 1H), 7.61-7.68 (m, 2H), 7.36 (br. s.,1H), 7.26-7.32 (m, 1H), 7.13 (br. s., 1H), 6.19 (br. s., 1H), 3.98 (s,3H), 3.91 (s, 3H), 3.52 (s, 3H); MS m/e 529.2 [M+H]⁺ and Example 3c:(second enantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃) δ8.31 (br. s., 1H), 7.79-8.05 (br. s., 1H), 7.78 (d, J=8.6 Hz, 1H),7.71-7.75 (m, 1H), 7.61-7.69 (m, 2H), 7.36 (br. s., 1H), 7.26-7.32 (m,1H), 7.12 (br. s., 1H), 6.19 (br. s., 1H), 3.98 (s, 3H), 3.91 (s, 3H),3.52 (s, 3H); MS m/e 529.2 [M+H]⁺.

Example 4a6-(Hydroxy(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrile

A round bottom flask was charged with(4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(96.6 mg, 0.183 mmol, Example 3a), Zn(CN)₂ (38.6 mg, 0.329 mmol),Pd₂(dba)₃ (25.1 mg, 0.027 mmol), zinc nanopowder (3.6 mg, 0.055 mmol),and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos, 18.0 mg, 0.037 mmol). The flask was evacuated and re-filledwith argon (three cycles). Dimethylacetamide (1.8 mL, sparged with argonfor 30 minutes) was then added and the mixture was heated at 120° C. for9 hours. The mixture was cooled to room temperature and was filteredthrough Celite®, washing with EtOAc. The filtrate was washedsequentially with 2 M aqueous NH₄OH, water, and saturated aqueous NaCl.The organic phase was dried (Na₂SO₄), filtered, and concentrated. Toimprove conversion, the crude product was resubjected to the reactionconditions as described above for an additional 4.5 hours, then wasworked up as described above. The residue was partially purified byflash column chromatography (silica gel, 2-8% MeOH-DCM) then was furtherpurified by RP-HPLC (10-90% CH₃CN—H₂O, 0.1% TFA). HPLC fractions werebasified (saturated aqueous NaHCO₃), partially concentrated, andextracted with DCM (3×). The organic extract was dried over Na₂SO₄,filtered, and concentrated to afford the title compound. MS m/e 519.9[M+H]⁺.6-(Hydroxy(1-methyl-1H-1,2,3-triazol-5-yl)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrilewas purified by chiral SFC (Chiralpack IC, 90% CO₂, 10% (0.2%isopropylamine-EtOH)) to give 2 enantiomers. The enantiomers were thenfurther purified on plug silica gel columns (0-5% MeOH-DCM). Example 4b:(first enantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃) δ8.27-8.31 (m, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 7.77-7.82 (m,1H), 7.73-7.77 (m, 1H), 7.66-7.73 (m, 1H), 7.35 (dd, J=8.6, 1.5 Hz, 1H),7.16 (s, 1H), 6.33 (br. s., 1H), 6.25 (br. s., 1H), 4.07 (s, 3H), 3.93(s, 3H), 3.53 (s, 3H); MS m/e 520.2 [M+H]⁺ and Example 4c: (secondenantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃) δ 8.29(d, J=2.0 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.84 (s, 1H), 7.77-7.81 (m,1H), 7.73-7.77 (m, 1H), 7.66-7.73 (m, 1H), 7.37 (dd, J=9.1, 2.0 Hz, 1H),7.33 (s, 1H), 7.19 (s, 1H), 6.30 (br. s., 1H), 5.54 (br. s., 1H), 4.08(s, 3H), 3.95 (s, 3H), 3.55 (s, 3H); MS m/e 520.0 [M+H]⁺.

Example 5(4-Chlorophenyl)(2,4-dichloro-3-(pyridin-2-yl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

Into a 100-mL round-bottom flask was placed a solution of6-bromo-2,4-dichloro-3-(pyridin-2-yl)quinoline (380 mg, 1.07 mmol,Intermediate 9: step c) in tetrahydrofuran (10 mL). This was followed bythe addition of n-BuLi (0.43 mL, 1.28 mmol, 3.0 M in hexanes) dropwisewith stirring at −78° C. The resulting solution was stirred for 30minutes at −78° C. To this was added a solution of5-[(4-chlorophenyl)carbonyl]-1-methyl-1H-imidazole (199 mg, 0.90 mmol,Intermediate 8: step b) in tetrahydrofuran (10 mL) dropwise withstirring at −78° C. The resulting solution was allowed to react, withstirring, for an additional 2 hours at room temperature. The reactionwas then quenched by the addition of 10 mL of saturated aqueous NH₄Cl.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC [(1#waters-2767-1): Column, Sunfire prep C18,5 μm, 19×100 mm; mobile phase, 0.05% TFA in water and MeOH (45% MeOH upto 65% in 10 minutes); Detector, UV 254 nm] to afford the title compoundtrifluoroacetic acid salt as a white solid. MS (ES, m/z) 495 [M+H]⁺; ¹HNMR (300 MHz, CDCl₃+D₂O) δ 8.86-8.69 (m, 1H), 8.50 (br. s., 1H), 8.40(br. s., 0.5H), 8.25 (br. s., 0.5H), 8.07 (d, J=8.6 Hz, 1H), 7.97 (t,J=7.5 Hz, 1H), 7.85-7.69 (m, 1H), 7.60-7.43 (m, 2H), 7.43-7.30 (m, 4H),6.70 (br. s., 0.5H), 6.65 (br. s., 0.5H), 3.59 (br. s., 3H).

Example 6(4-Chlorophenyl)(2,4-dichloro-3-(pyridin-3-yl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of6-bromo-2,4-dichloro-3-(pyridin-3-yl)quinoline (160 mg, 0.45 mmol,Intermediate 10: step c) in tetrahydrofuran (10 mL). This was followedby the addition of t-BuLi (0.85 mL, 1.35 mmol, 1.6 M in pentane)dropwise with stirring at −78° C. The resulting solution was stirred for30 minutes at −78° C. To this was added a solution of5-[(4-chlorophenyl)carbonyl]-1-methyl-1H-imidazole (121 mg, 0.55 mmol,Intermediate 8, step b) in tetrahydrofuran (10 mL) dropwise withstirring at −78° C. The resulting solution was stirred for 30 minutes at−78° C. The resulting solution was allowed to react, with stirring, foran additional 30 minutes at −40° C. The resulting solution was allowedto react, with stirring overnight at room temperature. The reaction wasthen quenched by the addition of 10 mL of saturated aqueous NH₄Cl. Theresulting solution was extracted with 3×10 mL of ethyl acetate and theorganic layers combined and dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude product was purifiedby Flash-Prep-HPLC [(IntelFlash-1): Column, silica gel; mobile phase,0.05% TFA in water and CH₃CN (22% CH₃CN up to 44% within 10 minutes;Detector, UV 254 nm] to afford the title compound trifluoroacetic acidsalt as an off-white solid. MS (ES, m/z) 495 [M+H]⁺ and 517 [M+Na]⁺; ¹HNMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.78-8.62 (m, 2H), 8.39-8.36 (m,1H), 8.15-8.07 (m, 2H), 7.97-7.94 (m, 1H), 7.80-7.76 (m, 1H), 7.54-7.45(m, 4H), 7.00 (br. s., 1H), 3.74 (d, J=11.2 Hz, 3H).

Example 7a{4-Chloro-2-methoxy-3-[4-(methylsulfonyl)phenyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol

A mixture of4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yltrifluoromethanesulfonate (70 mg, 0.12 mmol, Intermediate 11: step g),(4-(methylsulfonyl)phenyl)boronic acid (35 mg, 0.18 mmol), PdCl₂(dppf)(9 mg, 0.012 mmol) and K₂CO₃ (16 mg, 0.12 mmol) was sparged withnitrogen three times. To this mixture was added 1,4-dioxane (2 mL) andwater (0.3 mL) and the suspension purged with nitrogen. The resultingsolution was heated to 65° C. for 15 hours. The reaction was allowed tocool to room temperature and concentrated to dryness. The residue wasdissolved in DMSO, filtered and purified by reverse-phase HPLC(acetonitrile/water+TFA). The acidic fractions were neutralized bydiluting with EtOAc and washing with saturated aqueous NaHCO₃ followedby water. The organics were dried (MgSO₄), filtered and concentrated todryness to provide the title compound. ¹H NMR (400 MHz, CD₃OD) δ8.79-8.76 (m, 1H), 8.24-8.20 (m, 1H), 8.08-8.05 (m, 2H), 8.05-8.01 (m,1H), 7.96-7.93 (m, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76-7.72 (m, 2H),7.65-7.62 (m, 2H), 6.35 (s, 1H), 4.00 (s, 3H), 3.49 (s, 3H), 3.20 (s,3H); MS (ESI): mass calcd. for C₂₈H₂₂ClF₃N₄O₄S, 602.1; m/z found, 603.2[M+H]⁺.

{4-Chloro-2-methoxy-3-[4-(methylsulfonyl)phenyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanolwas purified by HPLC (Kromasil C18 100 Å, 5 column, Mobile phase:35-100% acetonitrile/water+0.25% ammonium bicarbonate) followed by FCC(0-5% MeOH/DCM) to give 2 enantiomers. The first eluting enantiomer wasExample 7b: ¹H NMR (400 MHz, CD₃OD) δ 8.81-8.77 (m, 1H), 8.23 (d, J=2.0Hz, 1H), 8.09-8.06 (m, 2H), 8.06-8.02 (m, 1H), 7.97-7.93 (m, 1H), 7.85(d, J=8.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.66-7.62 (m, 2H), 6.37 (s, 1H),4.01 (s, 3H), 3.50 (s, 3H), 3.21 (s, 3H); MS (ESI): mass calcd. forC₂₈H₂₂ClF₃N₄O₄S, 602.1; m/z found, 603.2 [M+H]⁺ and the second elutingenantiomer was Example 7c: ¹H NMR (400 MHz, CD₃OD) δ 8.80-8.77 (m, 1H),8.22 (d, J=2.1 Hz, 1H), 8.09-8.05 (m, 2H), 8.05-8.01 (m, 1H), 7.96-7.92(m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.77-7.71 (m, 2H), 7.66-7.61 (m, 2H),6.36 (s, 1H), 4.00 (s, 3H), 3.49 (s, 3H), 3.21 (s, 3H); MS (ESI): masscalcd. for C₂₈H₂₂ClF₃N₄O₄S, 602.1; m/z found, 603.2 [M+H]⁺.

Example 8[4-Chloro-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl](1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

The title compound was prepared using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inplace of (4-(methylsulfonyl)phenyl)boronic acid using the proceduredescribed for Example 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.82(d, J=2.3 Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.10-8.06 (m, 1H), 8.03 (s,1H), 7.93 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.85 (s, 1H), 7.66(dd, J=8.7, 2.1 Hz, 1H), 7.08-7.06 (m, 1H), 4.09 (s, 3H), 3.98 (s, 3H),3.71 (s, 3H); MS (ESI): mass calcd. for C₂₅H₂₀ClF₃N₆O₂, 528.1; m/zfound, 529.2 [M+H]⁺.

Example 9a5-(4-Chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)pyrimidine-2-carbonitrile.TFA

The title compound was prepared using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrilein place of (4-(methyl sulfonyl)phenyl)boronic acid using the proceduredescribed for Example 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.06-9.02 (m, 3H),8.84-8.79 (m, 1H), 8.33-8.29 (m, 1H), 8.12-8.08 (m, 1H), 8.02 (d, J=8.9Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.82-7.77 (m, 1H), 7.10 (s, 1H), 4.06(s, 3H), 3.71 (s, 3H); MS (ESI): mass calcd. for C₂₆H₁₇ClF₃N₇O₂, 551.1;m/z found, 552.2 [M+H]⁺.

5-(4-Chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)pyrimidine-2-carbonitrilewas purified by HPLC (CHIRACEL OD 20 Daicel column, Mobile phase: 100%EtOH) followed by FCC (0-10% MeOH/DCM) to give 2 enantiomers. The firsteluting enantiomer was Example 9b: ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s,2H), 8.77 (m, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.2, 2.2 Hz, 1H),7.98-7.94 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.79 (dd, J=8.9, 2.1 Hz, 1H),7.76-7.72 (m, 1H), 6.36 (s, 1H), 4.05 (s, 3H), 3.48 (s, 3H); MS (ESI):mass calcd. for C₂₆H₁₇ClF₃N₇O₂, 551.1; m/z found, 552.2 [M+H]⁺ and thesecond eluting enantiomer was Example 9c: ¹H NMR (400 MHz, CD₃OD) δ 9.05(s, 2H), 8.80-8.76 (m, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.06-8.02 (m, 1H),7.97 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.79 (dd, J=8.9, 2.1 Hz,1H), 7.75 (s, 1H), 6.36 (s, 1H), 4.06 (s, 3H), 3.49 (s, 3H); MS (ESI):mass calcd. for C₂₆H₁₇ClF₃N₇O₂, 551.1; m/z found, 552.2 [M+H]⁺.

Example 10(4-Chloro-2-methoxy-3-pyrimidin-5-ylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

The title compound was prepared using pyrimidin-5-ylboronic acid inplace of (4-(methylsulfonyl)phenyl)boronic acid using the proceduredescribed for Example 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 9.04(s, 1H), 8.88 (s, 2H), 8.84-8.81 (m, 1H), 8.32-8.28 (m, 1H), 8.12-8.08(m, 1H), 8.03-8.00 (m, 1H), 7.92-7.88 (m, 1H), 7.80-7.76 (m, 1H),7.11-7.09 (m, 1H), 4.05 (s, 3H), 3.72 (s, 3H); MS (ESI): mass calcd. forC₂₅H₁₈ClF₃N₆O₂, 526.1; m/z found, 527.1 [M+H]⁺.

Example 11{4-Chloro-2-methoxy-3-[3-(methylsulfonyl)phenyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

The title compound was prepared using (3-(methylsulfonyl)phenyl)boronicacid in place of (4-(methylsulfonyl)phenyl)boronic acid using theprocedure described for Example 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.02 (s,1H), 8.84-8.81 (m, 1H), 8.30-8.27 (m, 1H), 8.12-8.07 (m, 1H), 8.06-8.03(m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.97-7.95 (m, 1H), 7.90 (d, J=8.2 Hz,1H), 7.79-7.71 (m, 3H), 7.10-7.07 (m, 1H), 4.02 (s, 3H), 3.72 (s, 3H),3.18 (s, 3H); MS (ESI): mass calcd. for C₂₈H₂₂ClF₃N₄O₄S, 602.1; m/zfound, 603.2 [M+H]⁺.

Example 12N-[3-(4-Chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)phenyl]methanesulfonamide.TFA

The title compound was prepared using(3-(methylsulfonamido)phenyl)boronic acid in place of(4-(methylsulfonyl)phenyl)boronic acid using the procedure described forExample 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.85-8.81 (m, 1H),8.27-8.24 (m, 1H), 8.11-8.06 (m, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.90 (d,J=8.3 Hz, 1H), 7.75-7.70 (m, 1H), 7.48-7.42 (m, 1H), 7.31-7.27 (m, 1H),7.26-7.23 (m, 1H), 7.14-7.10 (m, 1H), 7.09-7.07 (m, 1H), 4.01 (s, 3H),3.72 (s, 3H), 2.99 (s, 3H); MS (ESI): mass calcd. for C₂₈H₂₃ClF₃N₅O₄S,617.1; m/z found, 618.0 [M+H]⁺.

Example 13{4-Chloro-2-methoxy-3-[5-(methylsulfonyl)pyridin-3-yl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

The title compound was prepared using(5-(methylsulfonyl)pyridin-3-yl)boronic acid in place of(4-(methylsulfonyl)phenyl)boronic acid using the procedure described forExample 7a. ¹H NMR (400 MHz, CD₃OD) δ 9.19-9.15 (m, 1H), 9.04 (s, 1H),8.91-8.87 (m, 1H), 8.82 (d, J=2.2 Hz, 1H), 8.46-8.43 (m, 1H), 8.31 (d,J=2.1 Hz, 1H), 8.13-8.08 (m, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.3Hz, 1H), 7.80-7.76 (m, 1H), 7.12-7.09 (m, 1H), 4.05 (s, 3H), 3.72 (s,3H), 3.28 (s, 3H); MS (ESI): mass calcd. for C₂₇H₂₁ClF₃N₅O₄S, 603.1; m/zfound, 604.0 [M+H]⁺.

Example 14a[4-Chloro-3-(5-chlorothiophen-2-yl)-2-methoxyquinolin-6-yl](1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

A mixture of4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yltrifluoromethanesulfonate (40 mg, 0.067 mmol, Intermediate 11: step g),(5-chlorothiophen-2-yl)boronic acid (16 mg, 0.1 mmol), PdCl₂(dppf) (5mg, 0.007 mmol) and K₂CO₃ (9 mg, 0.067 mmol) was sparged with nitrogenthree times. To this mixture was added 1,4-dioxane (1.2 mL) and water(0.17 mL) and the suspension purged with nitrogen. The resultingsolution was heated to 65° C. for 15 hours. The mixture was then heatedto 75° C. for 6 hours after which it was allowed to cool to roomtemperature. The solution was diluted with EtOAc, washed with water,dried (MgSO₄), filtered and concentrated to dryness. The crude materialwas purified by reverse-phase HPLC (acetonitrile/water+TFA) to providethe title compound. ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.84-8.81(m, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.11-8.06 (m, 1H), 7.96 (d, J=8.7 Hz,1H), 7.90 (d, J=8.2 Hz, 1H), 7.74-7.71 (m, 1H), 7.09-7.04 (m, 3H), 4.06(s, 3H), 3.71 (s, 3H); MS (ESI): mass calcd. for C₂₅H₁₇O₂F₃N₄O₂S, 564.0;m/z found, 565.0 [M+H]⁺.

[4-Chloro-3-(5-chlorothiophen-2-yl)-2-methoxyquinolin-6-yl](1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanolwas purified by HPLC (Kromasil C18 100 Å, 5 column, Mobile phase:35-100% acetonitrile/water+0.25% ammonium bicarbonate) to give 2enantiomers. The first eluting enantiomer was Example 14b: ¹H NMR (400MHz, CD₃OD) δ 8.79-8.77 (m, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.04-8.00 (m,1H), 7.90 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.72(dd, J=8.8, 2.1 Hz, 1H), 7.08-7.06 (m, 1H), 7.05-7.02 (m, 1H), 6.36-6.34(m, 1H), 4.05 (s, 3H), 3.48 (s, 3H); MS (ESI): mass calcd. forC₂₅H₁₇Cl₂F₃N₄O₂S, 564.0; m/z found, 565.0 [M+H]⁺ and the second elutingenantiomer was Example 14c: ¹H NMR (400 MHz, CD₃OD) δ 8.80-8.76 (m, 1H),8.21 (d, J=2.1 Hz, 1H), 8.05-8.00 (m, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.84(d, J=8.2 Hz, 1H), 7.75 (s, 1H), 7.74-7.70 (m, 1H), 7.08-7.06 (m, 1H),7.06-7.03 (m, 1H), 6.37-6.34 (m, 1H), 4.05 (s, 3H), 3.48 (s, 3H); MS(ESI): mass calcd. for C₂₅H₁₇Cl₂F₃N₄O₂S, 564.0; m/z found, 565.0 [M+H]⁺.

Example 15[4-Chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)quinolin-6-yl](1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

The title compound was prepared using (2-methoxypyrimidin-5-yl)boronicacid in place of (5-chlorothiophen-2-yl)boronic acid using the proceduredescribed for Example 14a. ¹H NMR (400 MHz, CD₃OD) δ 9.05-9.02 (m, 1H),8.84-8.80 (m, 1H), 8.63 (s, 2H), 8.28 (d, J=2.2 Hz, 1H), 8.12-8.08 (m,1H), 8.00 (d, J=8.7 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.78-7.73 (m, 1H),7.11-7.08 (m, 1H), 4.09 (s, 3H), 4.05 (s, 3H), 3.72 (s, 3H); MS (ESI):mass calcd. for C₂₆H₂₀ClF₃N₆O₃, 556.1; m/z found, 557.1 [M+H]⁺.

Example 164-(4-Chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)benzonitrile.TFA

The title compound was prepared using (4-cyanophenyl)boronic acid inplace of (5-chlorothiophen-2-yl)boronic acid using the proceduredescribed for Example 14a. ¹H NMR (400 MHz, CD₃OD) δ 9.05-9.03 (m, 1H),8.84-8.80 (m, 1H), 8.27 (d, J=2.3 Hz, 1H), 8.11-8.07 (m, 1H), 8.00 (d,J=8.7 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.87-7.83 (m, 2H), 7.74 (dd,J=8.8, 2.2 Hz, 1H), 7.57-7.53 (m, 2H), 7.10-7.07 (m, 1H), 4.00 (s, 3H),3.72 (s, 3H); MS (ESI): mass calcd. for C₂₈H₁₉ClF₃N₅O₂, 549.1; m/zfound, 550.2 [M+H]⁺.

Example 17N-[4-(4-Chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)phenyl]methanesulfonamide.TFA

The title compound was prepared using(4-(methylsulfonamido)phenyl)boronic acid in place of(5-chlorothiophen-2-yl)boronic acid using the procedure described forExample 14a. ¹H NMR (400 MHz, CD₃OD) δ 9.05-9.03 (m, 1H), 8.84-8.81 (m,1H), 8.25 (d, J=2.1 Hz, 1H), 8.11-8.06 (m, 1H), 7.97 (d, J=8.6 Hz, 1H),7.90 (d, J=8.3 Hz, 1H), 7.73-7.69 (m, 1H), 7.37-7.30 (m, 4H), 7.09-7.06(m, 1H), 4.00 (s, 3H), 3.72 (s, 3H), 3.04 (s, 3H); MS (ESI): mass calcd.for C₂₈H₂₃ClF₃N₅O₄S, 617.1; m/z found, 618.2 [M+H]⁺.

Example 18a6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methyl)-3-phenylquinoline-2,4-dicarbonitrile

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol(227.8 mg, 0.494 mmol, Example 64), zinc cyanide (73.8 mg, 0.628 mmol),zinc dust (8.8 mg, 0.135 mmol), dppf (27.7 mg, 0.05 mmol), and Pd₂(dba)₃(22.6 mg, 0.0247 mmol) were charged to an oven-dried microwave vial. Thevial was evacuated and back-filled with nitrogen. Dimethylacetamide (3mL) was added to the mixture via syringe. Nitrogen was bubbled throughthe reaction mixture for 5 minutes and the mixture was stirred andheated at 120° C. for 1 hour, followed by 100° C. for 3 hours under apositive pressure of nitrogen. The mixture was allowed to cool toambient temperature, filtered through Celite®, and rinsed with ethylacetate. The filtrate was basified with 5 M aqueous ammonium hydroxide,the layers were separated and the aqueous layer was extracted withexcess ethyl acetate. The combined organic layers were dried (Na₂SO₄),filtered, and concentrated to dryness. Due to an incomplete reaction asshown by LCMS (starting material and mono-cynated product present), thecrude material was subjected to additional reaction conditions. In anoven-dried microwave vial, the dry crude material was mixed with zinccyanide (80.1 mg, 0.682 mmol), zinc dust (8.7 mg, 0.133 mmol), X-Phos(32.7 mg, 0.0665 mmol), and Pd₂(dba)₃ (62.2 mg, 0.0679 mmol). The vialwas evacuated and back-filled with nitrogen. Dimethylacetamide (3.4 mL)was added to the mixture via syringe. Nitrogen was bubbled through thereaction mixture for 5 minutes and the mixture was stirred and heated at120° C. for 1.25 hours under a positive pressure of nitrogen. Themixture was allowed to cool to ambient temperature, filtered throughCelite®, and rinsed with ethyl acetate. The filtrate was basified with 5M aqueous ammonium hydroxide, the layers were separated and the aqueouslayer was extracted with excess ethyl acetate. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated to dryness. Thecrude product was purified by flash column chromatography (silica gel,0-5% MeOH-DCM) followed by reverse phase chromatography(acetonitrile/H₂O+0.05% TFA). Product fractions were basified withsaturated aqueous sodium bicarbonate and extracted with DCM, beforebeing dried (Na₂SO₄), filtered, and concentrated to provide the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J=4.5 Hz, 1H), 8.41 (d,J=1.8 Hz, 1H), 8.27 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.9, 1.9 Hz, 1H),7.78 (td, J=7.7, 1.7 Hz, 1H), 7.64-7.58 (m, 5H), 7.48 (s, 1H), 7.38-7.35(m, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.40 (s, 1H), 3.41 (s,3H); MS m/e 443.2 [M+H]⁺.

6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methyl)-3-phenylquinoline-2,4-dicarbonitrilewas purified by chiral SFC (ChiralPak AD, 100% ethanol) to provide twopure enantiomers. The first eluting enantiomer was Example 18b: ¹H NMR(500 MHz, CDCl₃) δ 8.66 (d, J=4.3 Hz, 1H), 8.41 (d, J=1.7 Hz, 1H), 8.28(d, J=8.9 Hz, 1H), 8.06 (dd, J=8.9, 1.9 Hz, 1H), 7.78 (td, J=7.7, 1.7Hz, 1H), 7.66-7.57 (m, 5H), 7.51 (s, 1H), 7.37 (ddd, J=7.5, 4.9, 0.8 Hz,1H), 7.30 (d, J=7.9 Hz, 1H), 6.82 (s, 1H), 6.41 (s, 1H), 3.42 (s, 3H);MS m/e 443.2 [M+H]⁺. The second eluting enantiomer was Example 18c: ¹HNMR (500 MHz, CDCl₃) δ 8.66 (d, J=4.8 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H),8.28 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.9, 1.9 Hz, 1H), 7.78 (td, J=7.7,1.6 Hz, 1H), 7.66-7.58 (m, 5H), 7.48 (s, 1H), 7.37 (dd, J=7.1, 5.2 Hz,1H), 7.29 (d, J=7.9 Hz, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 3.41 (s, 3H);MS m/e 443.2 [M+H]⁺.

Example 19a6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline-4-carbonitrile

To a round bottom flask containing(4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(0.19 g, 0.305 mmol, Example 63) was added Zn(CN)₂ (64.47 mg, 0.596mmol), Pd₂(dba)₃ (41.9 mg, 0.046 mmol), zinc nanopowder (5.9 mg, 0.092mmol), anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos, 29.9 mg, 0.061 mmol). The flask was evacuated and re-filledwith argon (3×). Dimethylacetamide (1.5 mL, degassed) was then added andthe mixture was heated at 120° C. for 4 hours. The mixture was cooled toroom temperature, diluted with EtOAc and filtered through Celite®rinsing with EtOAc. The filtrate was diluted with saturated aqueousNH₄Cl and H₂O and layers were separated. The aqueous layer was againextracted with EtOAc. The combined EtOAc extract was washed with brine,dried over Na₂SO₄, filtered and evaporated in vacuo to provide an oil.LC/MS showed product plus a significant amount of starting material. Themixture was re-subjected to the conditions above and heated in a 120° C.oil bath for an additional 4 hours. After work-up (same as above) thecrude product was purified by chromatography (10% MeOH in DCM on agradient) to provide the title compound.

6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline-4-carbonitrilewas purified by chiral HPLC (Chiralpak (IC); solvent A=CO₂; solventB=methanol+0.2% IPA; flow rate 50 mL/min; wavelength 254 nM; temperature40 degrees) to give 2 enantiomers. The first eluting enantiomer wasExample 19b: ¹H NMR (400 MHz, CDCl₃) δ 8.74-8.87 (m, 1H), 8.06-8.16 (m,1H), 7.91-8.02 (m, 1H), 7.65-7.74 (m, 1H), 7.54-7.65 (m, 2H), 7.42-7.52(m, 2H), 7.32-7.41 (m, 2H), 6.44-6.60 (m, 1H), 4.09 (s, 3H), 3.28-3.51(s, 3H), 2.67 (s, 3H); MS (ESI) 614 (M+H)⁺. The second elutingenantiomer was Example 19c: ¹H NMR (400 MHz, CDCl₃) δ 8.75-8.86 (m, 1H),8.05-8.16 (m, 1H), 7.89-8.02 (m, 1H), 7.65-7.77 (m, 1H), 7.54-7.63 (m,2H), 7.42-7.50 (m, 2H), 7.32-7.42 (m, 2H), 6.40-6.60 (m, 1H), 4.08 (s,3H), 3.35-3.56 (broad s, 3H), 2.68 (s, 3H); MS (ESI) 614 (M+H)⁺.

Example 201-(4-((2,4-Dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(phenyl)methyl)piperidin-1-yl)ethanone

A solution of n-butyllithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) wasadded dropwise by syringe to a solution of6-bromo-2,4-dichloro-8-methyl-3-phenylquinoline (0.32 g, 0.88 mmol,Intermediate 3) in dry deoxygenated THF (10 mL) at −78° C. After 2minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (0.203 g,0.88 mmol, Intermediate 4) in dry THF (4 mL) was added dropwise bysyringe. An additional 2 mL of THF was used to complete the quantitativeaddition. After 10 minutes, the flask was removed from the dry-ice bathand placed into an ice-water bath. After 1 hour, the reaction wasquenched with saturated aqueous ammonium chloride solution and themixture was partitioned between water and EtOAc. The layers wereseparated and the aqueous phase was further extracted with EtOAc andwashed with saturated aqueous NaCl solution. The organic phase was dried(MgSO₄), filtered, and concentrated to dryness. The crude product waspurified by flash column chromatography (silica gel, 0-100% EtOAc-DCM)to provide the title compound. MS m/e 519.1 (M+H)⁺.

Example 21a6-((1-Acetylpiperidin-4-yl)(hydroxy)(phenyl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrile

A microwave vial was charged with1-(4-((2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(phenyl)methyl)piperidin-1-yl)ethanone(240 mg, 0.46 mmol, Example 20), Zn(CN)₂ (55.7 mg, 0.480 mmol),Pd₂(dba)₃ (43.3 mg, 0.047 mmol), zinc dust (6.05 mg, 0.0926 mmol), anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos, 22.1 mg, 0.046 mmol). Dimethylacetamide (2.4 mL) was then addedand the mixture was sparged with nitrogen for 10 minutes and placed in apre-heated aluminum block at 120° C. for 2 hours. The mixture was cooledto room temperature and was filtered through Celite®, and washed withEtOAc. The filtrate was washed sequentially with 2 M aqueous NH₄OH andaqueous NaCl solution. The organic phase was dried (MgSO₄), filtered,and concentrated. The residue was purified by flash columnchromatography (silica gel, 0 to 100% EtOAc-DCM). MS (ESI) 501.3 (M+H)⁺.

6-((1-Acetylpiperidin-4-yl)(hydroxy)(phenyl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrilewas purified by chiral HPLC (Chiralcel OD, 80% heptane/20% ethanol) togive 2 enantiomers. The 2 enantiomers were further purified byreverse-phase HPLC (5-85% CH₃CN—H₂O, 0.05% TFA). The product wasconverted to the free base (neutralized with saturated aqueous NaHCO₃and extracted with EtOAc) and the organic fractions were concentrated toafford the title compound. The first eluting enantiomer was Example 21b:¹H NMR (600 MHz, CDCl₃, mixture of rotamers) δ ppm 8.35-8.32 (m, 1H),7.84-7.81 (m, 1H), 7.66-7.59 (m, 5H), 7.58-7.55 (m, 2H), 7.41-7.37 (m,2H), 7.31-7.24 (m, 1H), 4.75 (d, J=13.4 Hz, 0.5H), 4.69 (d, J=13.5 Hz,0.5H), 3.89 (d, J=13.7 Hz, 0.5H), 3.82 (d, J=13.7 Hz, 0.5H), 3.16 (t,J=12.2 Hz, 0.5H), 3.12-3.03 (m, 0.5H), 2.89-2.83 (m, 1H), 2.82 (s,1.5H), 2.80 (s, 1.5H), 2.67-2.53 (m, 1H), 2.38 (s, 0.5H), 2.36 (s,0.5H), 2.07 (s, 1.5H), 2.06 (s, 1.5H), 1.46-1.21 (m, 4H); MS m/e 501.2[M+H]⁺ and the second eluting enantiomer was Example 21c: ¹H NMR (600MHz, CDCl₃, mixture of rotamers) δ ppm 8.35-8.32 (m, 1H), 7.84-7.81 (m,1H), 7.65-7.59 (m, 5H), 7.58-7.55 (m, 2H), 7.41-7.37 (m, 2H), 7.31-7.24(m, 1H), 4.75 (d, J=13.5 Hz, 0.5H), 4.69 (d, J=13.5 Hz, 0.5H), 3.89 (d,J=13.7 Hz, 0.5H), 3.82 (d, J=13.6 Hz, 0.5H), 3.18-3.14 (m, 0.5H),3.11-3.07 (m, 0.5H), 2.86-2.83 (m, 1H), 2.82 (s, 1.5H), 2.80 (s, 1.5H),2.68-2.54 (m, 1H), 2.37 (s, 0.5H), 2.35 (s, 0.5H), 2.07 (s, 1.5H), 2.06(s, 1.5H), 1.47-1.21 (m, 4H); MS m/e 501.2 [M+H]⁺.

Example 22(4-Chlorophenyl)(2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol

The title compound was prepared analogously to the method described inExample 20 using (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone(Intermediate 8: step b) in place of 1-(4-benzoylpiperidin-1-yl)ethanone(Intermediate 4). MS m/e 508.1 (M+H)⁺.

Example 23a6-((4-Chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrile

The title compound was prepared analogously to the method described inExample 21a using(4-chlorophenyl)(2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(Example 22) in place of1-(4-((2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(phenyl)methyl)piperidin-1-yl)ethanone(Example 20). MS m/e 490.2 (M+H)⁺.

6-(4-Chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrilewas purified by chiral HPLC (Chiralcel OD, 50% heptane/20% ethanol) togive 2 enantiomers. The 2 enantiomers were further purified byreverse-phase HPLC (5-85% CH₃CN—H₂O, 0.05% TFA). The product wasconverted to the free base (neutralized with saturated aqueous NaHCO₃and extracted with EtOAc) and the organic fractions were concentrated toafford the title compound. The first eluting enantiomer was Example 23b:¹H NMR (600 MHz, CDCl₃) δ ppm 8.21 (s, 1H), 7.62-7.49 (m, 6H), 7.24 (s,5H), 6.29 (s, 1H), 3.32 (s, 3H), 2.70 (s, 3H); MS m/e 490.2 [M+H]⁺ andthe second eluting enantiomer was Example 23c: ¹H NMR (600 MHz, CDCl₃) δppm 8.29 (d, J=1.5 Hz, 1H), 7.67-7.56 (m, 6H), 7.35-7.28 (m, 4H), 7.14(s, 1H), 6.27 (s, 1H), 3.35 (s, 3H), 2.75 (s, 3H); MS m/e 490.2 [M+H]⁺.

Example 24(2,4-Dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

The title compound was prepared analogously to the method described inExample 20 using(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(Intermediate 2: step c) in place of 1-(4-benzoylpiperidin-1-yl)ethanone(Intermediate 4). MS m/e 543.1 (M+H)⁺.

Example 25a6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrile

The title compound was prepared analogously to the method described inExample 21a using(2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(Example 24) in place of1-(4-((2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(phenyl)methyl)piperidin-1-yl)ethanone(Example 20). MS m/e 525.2 (M+H)⁺.

6-(Hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrilewas purified by chiral HPLC (Chiralcel OD, 80% heptane/20% ethanol) togive 2 enantiomers. The first eluting enantiomer was Example 25b: ¹H NMR(600 MHz, CDCl₃) δ ppm 8.81 (d, J=2.1 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H),7.98 (dd, J=8.3, 2.2 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.66-7.59 (m, 6H),7.37 (s, 1H), 6.45 (s, 1H), 5.29 (s, 1H), 3.41 (s, 3H), 2.80 (s, 3H); MSm/e 525.2 (M+H)⁺ and the second eluting enantiomer was Example 25c: ¹HNMR (600 MHz, CDCl₃) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.33 (dd, J=2.2, 0.7Hz, 1H), 7.97 (dd, J=8.3, 2.2 Hz, 1H), 7.70 (dd, J=8.2, 0.8 Hz, 1H),7.67-7.58 (m, 6H), 7.31 (s, 1H), 6.38 (d, J=1.2 Hz, 1H), 5.94 (s, 1H),3.39 (s, 3H), 2.79 (s, 3H); MS m/e 525.2 (M+H)⁺.

Example 261-(4-((2,4-Dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-1-yl)ethanone

The title compound was prepared analogously to the method described inExample 20 using1-(4-(6-(trifluoromethyl)nicotinoyl)piperidin-1-yl)ethanone(Intermediate 14: step d) in place of1-(4-benzoylpiperidin-1-yl)ethanone (Intermediate 4). MS m/e 588.2(M+H)⁺.

Example 27a6-((1-Acetylpiperidin-4-yl)(hydroxy)(6-(trifluoromethyl)pyridin-3-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrile

The title compound was prepared analogously to the method described inExample 21a using1-(4-((2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(hydroxy)(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-1-yl)ethanone(Example 26). MS m/e 570.3 (M+H)⁺.

6-((1-Acetylpiperidin-4-yl)(hydroxy)(6-(trifluoromethyl)pyridin-3-yl)methyl)-8-methyl-3-phenylquinoline-2,4-dicarbonitrilewas purified by chiral SFC (Chiralpak AD-H, 5 μm, 250×20 mm, mobilephase: 75% CO₂, 25% mixture of methanol-isopropanol 50/50 v/v). Thefirst eluting enantiomer was Example 27b: ¹H NMR (600 MHz, CDCl₃,mixture of rotamers) δ ppm 8.98-8.94 (m, 1H), 8.41-8.32 (m, 1H),8.16-8.13 (m, 1H), 7.87 (s, 0.5H), 7.79 (s, 0.5H), 7.71-7.66 (m, 1H),7.65-7.56 (m, 5H), 4.74-4.68 (m, 1H), 3.96-3.64 (m, 2H), 3.21-3.08 (m,1H), 2.93-2.88 (m, 1H), 2.84 (s, 1.5H), 2.83 (s, 1.5H), 2.65-2.60 (m,1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.58-1.34 (m, 4H); MS m/e 570.3(M+H)⁺ and the second eluting enantiomer was Example 27c: ¹H NMR (600MHz, CDCl₃, mixture of rotamers) δ ppm 9.01-8.93 (m, 1H), 8.39-8.36 (m,1H), 8.16-8.13 (m, 1H), 7.87 (s, 0.5H), 7.79 (s, 0.5H), 7.69-7.67 (m,1H), 7.66-7.58 (m, 5H), 4.74-4.68 (m, 1H), 3.97-3.64 (m, 2H), 3.22-3.06(m, 1H), 2.93-2.88 (m, 1H), 2.84 (s, 1.5H), 2.83 (s, 1.5H), 2.70-2.53(m, 1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H) 1.58-1.34 (m, 4H); MS m/e 570.3(M+H)⁺.

Example 286-((4-Cyanophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenyl-2-(trifluoromethyl)quinoline-4-carbonitrile.TFA

The title compound was isolated from the reaction that formed Example31a. ¹H NMR (400 MHz, CD₃OD) δ 9.04 (s, 1H), 8.40 (d, J=9.09 Hz, 1H),8.34 (d, J=2.02 Hz, 1H), 8.06 (dd, J=2.27, 8.84 Hz, 1H), 7.84 (d, J=8.59Hz, 2H), 7.70 (d, J=8.59 Hz, 2H), 7.54-7.60 (m, 3H), 7.43-7.49 (m, 2H),7.09 (d, J=1.52 Hz, 1H), 3.70 (s, 3H); MS m/e 510.1 [M+H]⁺.

Example 291-(4-((4-Chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidin-1-yl)ethanone.TFA

A mixture of(4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(piperidin-4-yl)(pyridin-3-yl)methanol(198 mg, 0.400 mmol, Example 70), acetyl chloride (0.060 mL, 0.84 mmol),and Et₃N (0.16 mL, 1.15 mmol) in CH₂Cl₂ (4 mL) was stirred at roomtemperature for 1.5 hours and then concentrated to dryness. The residuewas purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) toprovide the title compound as a white solid. ¹H NMR (400 MHz, CD₃OD) δ9.13 (s, 1H), 8.82 (t, J=8.08 Hz, 1H), 8.69-8.75 (m, 2H), 8.27 (d,J=9.09 Hz, 1H), 8.18-8.24 (m, 1H), 7.94-8.02 (m, 1H), 7.49-7.55 (m, 3H),7.26-7.34 (m, 2H), 4.55-4.65 (m, 1H), 3.91-4.05 (m, 1H), 3.15-3.27 (m,2H), 2.67-2.77 (m, 1H), 2.08 (d, J=4.04 Hz, 3H), 1.52 (m, 4H); MS m/e540.3 [M+H]⁺.

Example 30a6-((1-Acetylpiperidin-4-yl)(hydroxy)(pyridin-3-yl)methyl)-3-phenyl-2-(trifluoromethyl)quinoline-4-carbonitrile.TFA

The title compound was prepared using1-(4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidin-1-yl)ethanone.TFA(Example 29) in place of(4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA(Example 62) using the procedure described for Example 31a, with theexception that the reaction mixture was heated at 120° C. for 10 hours.¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.87-8.93 (m, 1H), 8.74 (d,J=5.56 Hz, 1H), 8.62 (dd, J=2.02, 5.56 Hz, 1H), 8.37 (d, J=9.09 Hz, 1H),8.25-8.32 (m, 1H), 8.00-8.07 (m, 1H), 7.53-7.62 (m, 3H), 7.41-7.50 (m,2H), 4.55-4.66 (m, 1H), 3.92-4.03 (m, 1H), 3.16-3.28 (m, 2H), 2.68-2.77(m, 1H), 2.08 (d, J=5.05 Hz, 3H), 1.41-1.67 (m, 4H); MS m/e 531.3[M+H]⁺.

6-((1-Acetylpiperidin-4-yl)(hydroxy)(pyridin-3-yl)methyl)-3-phenyl-2-(trifluoromethyl)quinoline-4-carbonitrilewas neutralized by partitioning between saturated NaHCO₃ aqueoussolution and DCM (×1) followed by EtOAc (×3). The organic layer wasdried (Na₂SO₄), filtered, concentrated to dryness, and purified bychiral HPLC (Chiralcel OD, CH₃CN) to give two pure enantiomers. Example30b: (first enantiomer to elute off chiral column) ¹H NMR (400 MHz,CDCl₃, ˜1:1 mixture of rotamers) δ 8.77-8.94 (m, 1H), 8.54 (dd, J=1.52,12.13 Hz, 1H), 8.38-8.50 (m, 1H), 8.29 (t, J=9.09 Hz, 1H), 8.07 (dd,J=2.02, 9.09 Hz, 0.5H), 7.99 (dd, J=2.02, 9.09 Hz, 0.5H), 7.95 (d,J=8.08 Hz, 1H), 7.47-7.65 (m, 3H), 7.36-7.42 (m, 2H), 7.19-7.34 (m, 1H),5.55-5.84 (m, 2H), 5.08-5.18 (m, 1H), 4.56-4.77 (m, 1H), 3.71-3.93 (m,1H), 3.00-3.21 (m, 1H), 2.78-2.96 (m, 1H), 2.52-2.66 (m, 1H), 1.37-1.75(m, 3H), 1.22-1.35 (m, 1H); MS m/e 531.3 [M+H]⁺. Example 30c: (secondenantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃, ˜1:1mixture of rotamers) δ 8.79-8.93 (m, 1H), 8.54 (dd, J=1.52, 11.62 Hz,1H), 8.40-8.50 (m, 1H), 8.29 (t, J=8.34 Hz, 1H), 8.06 (dd, J=2.02, 9.09Hz, 0.5H), 7.99 (dd, J=2.02, 9.09 Hz, 0.5H), 7.94 (d, J=8.08 Hz, 1H),7.51-7.59 (m, 3H), 7.36-7.44 (m, 2H), 7.25-7.34 (m, 1H), 5.62-5.95 (m,2H), 4.93-5.03 (m, 1H), 4.59-4.76 (m, 1H), 3.76-3.90 (m, 1H), 3.03-3.20(m, 1H), 2.80-2.93 (m, 1H), 2.52-2.68 (m, 1H), 1.36-1.74 (m, 3H),1.20-1.36 (m, 1H); MS m/e 531.3 [M+H]⁺.

Example 31a6-((4-Chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenyl-2-(trifluoromethyl)quinoline-4-carbonitrile.TFA

A pressure tube containing(4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA(145 mg, 0.190 mmol, Example 62), Pd₂(dba)₃ (18 mg, 0.020 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos, 10 mg, 0.021 mmol), zinc cyanide (11.5 mg, 0.098 mmol), andzinc nanopowder (2.5 mg, 0.038 mmol) in N,N-dimethylacetamide (1 mL) wassparged with nitrogen for 8 minutes, and then heated at 120° C. for 2.5hours. The mixture was allowed to cool to room temperature and filteredthrough a syringe filter. The filtrate was concentrated in vacuo, EtOAcand saturated NH₄Cl aqueous solution were added. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated todryness. The residue was purified by reverse phase HPLC(water/acetonitrile/0.1% TFA) to provide the title compound as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 9.02 (s, 1H), 8.39 (d, J=8.59 Hz, 1H),8.34 (d, J=2.02 Hz, 1H), 8.05 (dd, J=2.27, 8.84 Hz, 1H), 7.52-7.63 (m,3H), 7.42-7.50 (m, 6H), 7.04 (s, 1H), 3.71 (s, 3H); MS m/e 519.2 [M+H]⁺.

6-(4-Chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenyl-2-(trifluoromethyl)quinoline-4-carbonitrilewas neutralized by partitioning between saturated NaHCO₃ aqueoussolution and DCM. The organic layer was dried (Na₂SO₄), filtered,concentrated to dryness, and purified by chiral HPLC (Chiralcel OD, 90%heptanes/10% EtOH) to give two pure enantiomers. Example 31b: (firstenantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃) δ 8.46(s, 1H), 8.23 (d, J=9.09 Hz, 1H), 7.78 (dd, J=2.02, 9.09 Hz, 1H),7.52-7.62 (m, 3H), 7.36-7.43 (m, 2H), 7.28-7.36 (m, 4H), 7.18-7.28 (m,1H), 6.29 (s, 1H), 3.37 (s, 3H); MS m/e 519.2 [M+H]⁺. Example 31c:(second enantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃) δ8.45 (s, 1H), 8.23 (d, J=9.09 Hz, 1H), 7.78 (d, J=9.09 Hz, 1H),7.50-7.64 (m, 3H), 7.35-7.43 (m, 2H), 7.27-7.35 (m, 4H), 7.19-7.28 (m,1H), 6.28 (s, 1H), 3.37 (s, 3H); MS m/e 519.2 [M+H]⁺.

Example 32a(4-Methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.TFA

A mixture of(4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.TFA(53 mg, 0.073 mmol, Example 61) and 0.5 M NaOMe in MeOH (0.80 mL, 0.40mmol) in a sealed tube was heated at 70° C. for 2 hours. The solvent wasevaporated, and water was added. The mixture was extracted with EtOAc,dried (Na₂SO₄), filtered, and concentrated. The residue was purified byreverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the titlecompound as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.96 (s, 1H), 8.62(d, J=4.04 Hz, 1H), 8.41 (d, J=2.02 Hz, 1H), 8.19 (d, J=9.09 Hz, 1H),8.02 (dd, J=2.02, 9.09 Hz, 1H), 7.93 (td, J=2.02, 8.08 Hz, 1H), 7.79 (d,J=8.08 Hz, 1H), 7.47-7.52 (m, 3H), 7.36-7.45 (m, 3H), 7.08 (d, J=1.52Hz, 1H), 3.63 (s, 3H), 3.55 (s, 3H); MS m/e 491.2 [M+H]⁺.

The racemate was neutralized by partitioning between saturated NaHCO₃aqueous solution and DCM. The organic layer was dried (Na₂SO₄),filtered, concentrated to dryness, and purified by chiral HPLC(Chiralcel OD, 90% heptanes/10% EtOH) to give two enantiomers. The firsteluting enantiomer was Example 32b: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d,J=4.55 Hz, 1H), 8.18-8.24 (m, 2H), 7.88 (dd, J=2.02, 9.09 Hz, 1H), 7.72(td, J=1.52, 7.58 Hz, 1H), 7.50 (s, 1H), 7.43-7.49 (m, 3H), 7.30-7.40(m, 3H), 7.23 (d, J=8.08 Hz, 1H), 6.37 (s, 1H), 3.50 (s, 3H), 3.44 (s,3H); MS m/e 491.2 [M+H]⁺.

Example 33a(4-Chlorophenyl)(4-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

A mixture of(4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA(80 mg, 0.11 mmol, Example 62) and 0.5 M NaOMe in MeOH (0.50 mL, 0.25mmol) in a sealed tube was heated at 70° C. for 7 hours. More 0.5 MNaOMe in MeOH (0.35 mL, 0.18 mmol) was added and the mixture was heatedat the same temperature for another hour. The solvent was evaporated,and DMSO was added. After filtering through a syringe filter, thefiltrate was purified by reverse phase HPLC (water/acetonitrile/0.1%TFA) to provide the title compound as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 9.00 (s, 1H), 8.25 (d, J=2.02 Hz, 1H), 8.23 (d, J=9.09 Hz, 1H),7.88 (dd, J=2.02, 9.09 Hz, 1H), 7.47-7.52 (m, 4H), 7.41-7.47 (m, 3H),7.36-7.41 (m, 2H), 6.97 (s, 1H), 3.71 (s, 3H), 3.53 (s, 3H); MS m/e524.3 [M+H]⁺.

(4-Chlorophenyl)(4-methoxy-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanolwas neutralized by partitioning between saturated NaHCO₃ aqueoussolution and DCM. The organic layer was dried (Na₂SO₄), filtered,concentrated to dryness, and purified by chiral HPLC (Chiralpak OJ, 100%MeOH) to give two enantiomers. The first eluting enantiomer was Example33b: ¹H NMR (400 MHz, CDCl₃) δ 8.14-8.20 (m, 2H), 7.77 (dd, J=2.27, 8.84Hz, 1H), 7.44-7.55 (m, 3H), 7.34-7.40 (m, 2H), 7.29-7.34 (m, 4H),7.24-7.29 (m, 1H), 6.34 (br. s., 1H), 3.48 (s, 3H), 3.36 (s, 3H); MS m/e524.3 [M+H]⁺ and the second eluting enantiomer was Example 33c: ¹H NMR(400 MHz, CDCl₃) δ 8.14-8.20 (m, 2H), 7.77 (dd, J=2.02, 9.09 Hz, 1H),7.44-7.50 (m, 3H), 7.36 (d, J=4.04 Hz, 2H), 7.29-7.34 (m, 4H), 7.23-7.29(m, 1H), 6.32-6.36 (m, 1H), 3.48 (s, 3H), 3.37 (s, 3H); MS m/e 524.1[M+H]⁺.

Example 34a1-(4-((4-Chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone

The racemic title compound was prepared using1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone(Intermediate 1: step c) in place of(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 8:step b) using the procedure described for Example 62, with the exceptionthat the reaction was carried out at −78° C. all the time. ¹H NMR (400MHz, CD₃OD, ˜1:1 mixture of rotamers) δ 8.86 (s, 1H), 8.56 (d, J=4.04Hz, 1H), 8.27 (d, J=9.09 Hz, 1H), 8.09 (s, 1H), 7.81 (d, J=9.09 Hz, 1H),7.45-7.58 (m, 3H), 7.31 (d, J=2.53 Hz, 2H), 4.66 (d, J=13.14 Hz, 0.5H),4.46 (d, J=12.63 Hz, 0.5H), 4.04 (d, J=13.64 Hz, 0.5H), 3.84 (d, J=13.64Hz, 0.5H), 3.60 (s, 1.5H), 3.58 (s, 1.5H), 3.25-3.30 (overlap withsolvent, m, 0.5H), 3.05 (td, J=2.53, 13.14 Hz, 0.5H), 2.67-2.86 (m,1.5H), 2.55 (td, J=3.03, 12.88 Hz, 0.5H), 2.09-2.28 (m, 1H), 2.08 (s,1.5H), 2.03 (s, 1.5H), 1.41-1.63 (m, 1H), 1.27-1.41 (m, 1H), 1.05-1.27(m, 1H); MS m/e 543.2 [M+H]⁺.

The racemate was neutralized by partitioning between saturated NaHCO₃aqueous solution and DCM. The organic layer was dried (Na₂SO₄),filtered, concentrated to dryness, and purified by chiral HPLC(Chiralcel OD, 100% EtOH) to give two pure enantiomers. Example 34b:(first enantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃,˜1.5:1 mixture of rotamers) δ 8.45 (d, J=13.64 Hz, 1H), 8.20 (dd,J=4.04, 8.59 Hz, 1H), 7.68 (t, J=10.11 Hz, 1H), 7.48-7.53 (m, 3H),7.24-7.34 (m, 2H), 7.10-7.24 (m, 2H), 4.65 (d, J=12.63 Hz, 0.6H), 4.56(d, J=13.14 Hz, 0.4H), 3.91 (d, J=13.14 Hz, 0.4H), 3.66-3.79 (m, 0.6H),3.31 (s, 1.8H), 3.29 (s, 1.2H), 3.18 (t, J=12.38 Hz, 0.4H), 2.97 (t,J=12.13 Hz, 0.6H), 2.38-2.69 (m, 2H), 2.34 (d, J=13.14 Hz, 0.4H), 2.22(d, J=12.63 Hz, 0.6H), 2.01 (s, 1.8H), 1.95 (s, 1.2H), 1.13-1.55 (m,2.4H), 1.09 (d, J=12.63 Hz, 0.6H); MS m/e 543.2 [M+H]⁺. Example 34c:(second enantiomer to elute off chiral column) ¹H NMR (400 MHz, CDCl₃,˜1.5:1 mixture of rotamers) δ 8.46 (d, J=12.63 Hz, 1H), 8.20 (dd,J=3.79, 8.84 Hz, 1H), 7.68 (t, J=10.11 Hz, 1H), 7.46-7.53 (m, 3H),7.24-7.35 (m, 2H), 7.10-7.23 (m, 2H), 4.64 (d, J=13.14 Hz, 0.6H), 4.55(d, J=12.63 Hz, 0.4H), 3.90 (d, J=13.14 Hz, 0.4H), 3.72 (d, J=13.14 Hz,0.6H), 3.31 (s, 1.8H), 3.29 (s, 1.2H), 3.18 (t, J=12.38 Hz, 0.4H), 2.97(t, J=12.38 Hz, 0.6H), 2.38-2.68 (m, 2H), 2.34 (d, J=12.63 Hz, 0.4H),2.21 (d, J=13.14 Hz, 0.6H), 2.01 (s, 1.8H), 1.94 (s, 1.2H), 1.12-1.58(m, 2.4H), 1.08 (d, J=12.63 Hz, 0.6H); MS m/e 543.2 [M+H]⁺.

Example 35(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol(100 mg, 0.2 mmol, Example 67) was added MeOH (6 mL) followed by solidNaOMe (50 mg, 0.88 mmol, 95% purity) at room temperature. The reactionmixture was heated to reflux for 24 hours, then allowed to cool to roomtemperature, filtered through Celite® and rinsed with MeOH. The MeOH wasremoved under reduced pressure and the residue was diluted with waterand extracted with EtOAc (3×40 mL). The combined organics were washedwith brine, dried over MgSO₄, filtered and concentrated to dryness.Purification by RP-HPLC (water/acetonitrile/0.05% TFA) afforded thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, J=2.1 Hz, 1H), 7.88(d, J=8.8 Hz, 1H), 7.57-7.39 (m, 4H), 7.38-7.30 (m, 2H), 7.17 (s, 1H),4.75 (s, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 2.56 (s, 3H), 2.12 (s, 3H); MS(ESI): mass calcd. for C₂₅H₂₂ClN₅O₂S, 491.1, m/z found 492.0 [M+H]⁺.

Example 36(2-Chloro-4-methoxy-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol(100 mg, 0.2 mmol, Example 67) was added MeOH (6 mL) followed by solidNaOMe (50 mg, 0.88 mmol, 95% purity) at room temperature. The reactionmixture was heated to reflux for 24 hours, then allowed to cool to roomtemperature, filtered through Celite® and rinsed with MeOH. The MeOH wasremoved under reduced pressure and the residue was diluted with waterand extracted with EtOAc (3×40 mL). The combined organics were washedwith brine, dried over MgSO₄, filtered and concentrated to dryness.Purification by RP-HPLC (water/acetonitrile/0.05% TFA) afforded thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 8.13 (d, J=2.1 Hz, 1H), 8.04(d, J=8.9 Hz, 1H), 7.68 (dd, J=8.9, 2.3 Hz, 1H), 7.54-7.44 (m, 3H),7.43-7.39 (m, 2H), 7.23 (s, 1H), 3.95 (br. s, 1H), 3.93 (s, 3H), 3.48(s, 3H), 2.59 (s, 3H), 2.16 (s, 3H); MS (ESI): mass calcd. forC₂₅H₂₂ClN₅O₂S, 491.1, m/z found 492.0 [M+H]⁺.

Example 37(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a microwave vial containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(120 mg, 0.24 mmol, Example 68) was added MeOH (4 mL) followed by solidNaOMe (60 mg, 1.11 mmol, 95% purity) at room temperature. The vial wassealed and evacuated and the mixture was heated to 75° C. for 5.5 hours.The MeOH was removed under reduced pressure and the residue was dilutedwith water and extracted with EtOAc (4×25 mL). The combined organicswere washed with brine, dried over MgSO₄, filtered and concentrated todryness. Purification by RP-HPLC (water/acetonitrile/0.05% TFA) affordedthe title compound. ¹H NMR (500 MHz, CD₃OD) δ 9.00 (s, 1H), 8.30 (d,J=2.0 Hz, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.81 (dd, J=8.9, 2.1 Hz, 1H),7.60-7.37 (m, 5H), 7.26 (s, 1H), 3.75 (s, 3H), 3.55 (s, 3H), 2.62 (s,3H), 2.25 (s, 3H); MS (ESI): mass calcd. for C₂₆H₂₃ClN₄O₂S, 490.1; m/zfound 491.1 [M+H]⁺.

Example 38(2-Chloro-4-methoxy-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a microwave vial containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(120 mg, 0.24 mmol, Example 68) was added MeOH (4 mL) followed by solidNaOMe (60 mg, 1.11 mmol, 95% purity) at room temperature. The vial wassealed and evacuated and the mixture was heated to 75° C. for 5.5 hours.The MeOH was removed under reduced pressure and the residue was dilutedwith water and extracted with EtOAc (4×25 mL). The combined organicswere washed with brine, dried over MgSO₄, filtered and concentrated todryness. Purification by RP-HPLC (water/acetonitrile/0.05% TFA) affordedthe title compound. ¹H NMR (500 MHz, CD₃OD) δ 9.00 (s, 1H), 8.28 (d,J=2.1 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.74 (dd, J=8.8, 2.2 Hz, 1H),7.51-7.38 (m, 3H), 7.35-7.27 (m, 2H), 7.24 (s, 1H), 4.00 (s, 3H), 3.75(s, 3H), 2.62 (s, 3H), 2.25 (s, 3H); MS (ESI): mass calcd. forC₂₆H₂₃ClN₄O₂S, 490.1; m/z found 491.1 [M+H]⁺.

Example 39(2,4-Dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a flask containing 1-methyl-1H-1,2,3-triazole (125 mg, 1.5 mmol) wasadded THF (10 mL) and the colorless solution was cooled to −45° C. Then,n-BuLi (2.5 M in hexanes, 0.6 mL, 1.5 mmol) was added affording asuspension. The suspension was stirred between −40° C. and −10° C. for30 minutes, then a THF solution of(2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone(500 mg, 1.26 mmol, Intermediate 18: step b, in 5 mL THF) was introducedand the mixture was allowed to warm up to room temperature. After 1hour, the reaction mixture was heated to 40° C. for 3 hours and thenquenched with aqueous NH₄Cl solution. The aqueous portion was extractedwith EtOAc (3×50 mL) and then with DCM (3×50 mL). The individual organicportions were washed with brine, dried over MgSO₄, filtered, combinedand concentrated to dryness. Chromatography on silica gel (5% MeOH-DCMincreasing to 10% MeOH) provided material which was re-purified bypreparative TLC (5% 2 M-NH₃-MeOH-EtOAc) to provide the title compound aslight tan solid. ¹H NMR (500 MHz, CDCl₃) δ 8.45-8.36 (m, 1H), 7.94 (d,J=8.8 Hz, 1H), 7.66-7.46 (m, 4H), 7.46-7.30 (m, 2H), 7.01 (s, 1H), 5.94(s, 1H), 3.91 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H). MS (ESI): mass calcd.for C₂₄H₂₀Cl₂N₆O, 478.1, m/z found 479.1 [M+H]⁺.

Example 40a(2-Chloro-4-methoxy-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol(1.1 g, 2.29 mmol, Example 39) was added MeOH (30 mL) followed by solidNaOMe (505 mg, 9.35 mmol, 95% purity) at room temperature. The mixturewas heated to 80° C. for 5 hours, then cooled back to room temperatureand the MeOH was removed under reduced pressure. The crude material waspassed through a plug of silica gel (5% MeOH-DCM) to afford a lightbrown solid. This material was further purified by RP-HPLC(water/acetonitrile/0.05% TFA) to afford the title compound. ¹H NMR (500MHz, CD₃OD) δ 8.34 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.67 (dd,J=8.8, 2.1 Hz, 1H), 7.58-7.36 (m, 6H), 6.90 (s, 1H), 4.01 (s, 3H), 3.69(s, 3H), 3.55 (s, 3H), 2.66 (s, 3H); MS (ESI): mass calcd. forC₂₅H₂₃ClN₆O₂, 474.2, m/z found 475.1 [M+H]⁺.

The racemic mixture was separated by chiral chromatography using[Chiralpak AD, 1000 A, 20 μM (Diacel), heptane:2-propanol (80:20 with0.2% TEA), to give two enantiomers. The first eluting enantiomer wasExample 40b and the second eluting enantiomer was Example 40c.

Example 41a(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol(1.1 g, 2.29 mmol, Example 39) was added MeOH (30 mL) followed by solidNaOMe (505 mg, 9.35 mmol, 95% purity) at room temperature. The mixturewas heated to 80° C. for 5 hours, then cooled back to room temperatureand the MeOH was removed under reduced pressure. The crude material waspassed through a plug of silica gel (5% MeOH-DCM) to afford a lightbrown solid. This material was further purified by RP-HPLC(water/acetonitrile/0.05% TFA) to afford the title compound. ¹H NMR (500MHz, CD₃OD) δ 8.32 (d, J=2.1 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.60 (dd,J=8.8, 2.2 Hz, 1H), 7.50-7.37 (m, 4H), 7.34-7.25 (m, 2H), 6.87 (s, 1H),4.00 (s, 3H), 3.99 (s, 3H), 3.70 (s, 3H), 2.67 (s, 3H); MS (ESI): masscalcd. for C₂₅H₂₃ClN₆O₂, 474.2, m/z found 475.1 [M+H]⁺.

The racemic mixture was separated by chiral chromatography using[Chiralpak AD, 1000 A, 20 μM (Diacel), heptane:2-propanol (75:25 with0.2% TEA), to give two enantiomers. The first eluting enantiomer wasExample 41b and the second eluting enantiomer was Example 41c.

Example 42(2,4-Bis(methylthio)-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(198 mg, 0.4 mmol, Example 68) was added DMF (67.5 mL) followed bysodium methanethiolate (37 mg, 0.53 mmol) at room temperature. After 15minutes, the reaction mixture was concentrated and chromatographeddirectly on silica gel (2% MeOH-DCM increasing to 5% MeOH) whichafforded a mixture of two products. This material was re-purified byRP-HPLC (water/acetonitrile/0.05% TFA) to provide the title compound. ¹HNMR (500 MHz, CDCl₃) δ 8.72 (s, 1H), 8.60 (s, 1H), 8.25 (d, J=8.3 Hz,1H), 7.77 (d, J=8.3 Hz, 1H), 7.59-7.45 (m, 3H), 7.39-7.28 (m, 2H), 7.20(s, 1H), 3.71 (s, 3H), 2.80 (s, 3H), 2.68 (s, 3H), 2.32 (s, 3H), 1.95(s, 3H); MS (ESI): mass calcd. for C₂₇H₂₆N₄OS₃, 518.1, m/z found 519.1[M+H]⁺.

Example 43(4-Chloro-2-(methylthio)-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

To a flask containing(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol(198 mg, 0.4 mmol, Example 68) was added DMF (67.5 mL) followed bysodium methanethiolate (37 mg, 0.53 mmol) at room temperature. After 15minutes, the reaction mixture was concentrated to dryness andchromatographed directly on silica gel (2% MeOH-DCM increasing to 5%MeOH) which afforded a mixture of two products. This material wasre-purified by RP-HPLC (water/acetonitrile/0.05% TFA) to provide thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 8.70 (s, 1H), 8.63 (s, 1H),8.12 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.56-7.43 (m, 3H), 7.34(d, J=7.1 Hz, 2H), 7.20 (s, 1H), 3.71 (s, 3H), 2.78 (s, 3H), 2.34 (s,3H), 1.94 (s, 3H); MS (ESI): mass calcd. for C₂₆H₂₃ClN₄OS₂, 506.1, m/zfound 507.0 [M+H]⁺.

Example 44[2-(2-Aziridin-1-ylethoxy)-4-chloro-3-phenylquinolin-6-yl](4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), 2-(aziridin-1-yl)ethanol (16.2 μL,0.20 mmol), toluene (2 mL), and sodium hydride (60% dispersion inmineral oil, 20.2 mg, 0.51 mmol) were combined in a round bottom flaskunder an N₂ atmosphere. The reaction solution was heated to reflux andrefluxed overnight, cooled and stirred at room temperature an additionalnight before workup. Reaction contents were transferred to a separatoryfunnel with EtOAc dilution, and extracted with saturated, aqueous NH₄Clthen saturated, aqueous NaHCO₃ solutions. The organic phase wasseparated then dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatography(silica gel, 0-10% DCM/MeOH) to afford the title compound. MS (ESI):mass calcd. for C₃₀H₂₆Cl₂N₄O₂, 544.1; m/z found, 545.1 [M+H]⁺; ¹H NMR(600 MHz, CD₃OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H),7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.31 (m, 1H), 7.28-7.23 (m,6H), 6.18 (d, J=1.1 Hz, 1H), 4.51-4.44 (m, 2H), 3.37 (s, 3H), 2.50-2.39(m, 2H), 1.48-1.37 (m, 2H), 0.97-0.94 (m, 2H).

Example 45(4-Chlorophenyl)[4-chloro-3-phenyl-2-(2,2,2-trifluoroethoxy)quinolin-6-yl](1-methyl-1H-imidazol-5-yl)methanol.TFA

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), 2,2,2-trifluoroethanol (14.5 μL, 0.202mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineraloil, 20 mg, 0.51 mmol) were combined in a round bottom flask under an N₂atmosphere. The reaction solution was heated to reflux and refluxedovernight. The reaction solution was cooled to room temperature thentransferred to a separatory funnel with EtOAc dilution, and extractedwith saturated, aqueous NH₄Cl then saturated, aqueous NaHCO₃ solutions.The organic phase was separated then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (silica gel, 0-10% DCM/MeOH) then viareverse phase chromatography using acetonitrile with 0.05%trifluoroacetic acid in water as eluent. The fractions from thepurification containing the desired product were transferred to aseparatory funnel with EtOAc and extracted with a saturated, aqueousNaHCO₃ solution. The aqueous layer was separated, extracted with EtOAc,then the combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure to provide the title compound. MS(ESI): mass calcd. for C₂₈H₂₀Cl₂F₃N₃O₂, 557.1; m/z found, 558.3 [M+H]⁺;¹H NMR (600 MHz, CDCl₃) δ ppm 8.38 (s, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.1 Hz, 1H), 7.52-7.43 (m, 3H),7.38-7.31 (m, 6H), 6.56 (s, 1H), 4.92 (q, J=8.4 Hz, 2H), 3.62 (s, 3H).

Example 462-[{4-Chloro-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-3-phenylquinolin-2-yl}(methyl)amino]ethanol.TFA

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), 2-(methylamino)ethanol (16.2 μL, 0.202mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineraloil, 28.3 mg, 0.707 mmol) were combined in a round bottom flask andheated at reflux for 48 hours under an N₂ atmosphere. The reactionsolution was then cooled to room temperature, diluted with EtOAc,transferred to a separatory funnel, extracted with saturated, aqueousNH₄Cl then saturated, aqueous NaHCO₃ solutions. The organic phase wasseparated then dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash column chromatography(silica gel, 0-10% DCM/MeOH) then further purified via reverse phasechromatography using acetonitrile with 0.05% trifluoroacetic acid inwater as eluent, then lyophilized to afford the title compound as atrifluoroacetate salt. MS (ESI): mass calcd. for C₂₉H₂₆Cl₂N₄O₂, 532.1;m/z found, 533.2 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.98 (s, 1H),8.22 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.55 (t,J=7.4 Hz, 2H), 7.50 (t, J=7.4 Hz, 1H), 7.47-7.39 (m, 6H), 6.93 (d, J=1.4Hz, 1H), 3.80-3.73 (m, 2H), 3.69 (s, 3H), 3.61-3.57 (m, 2H), 2.75 (s,3H).

Example 47a6-((2,4-Dimethylthiazol-5-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)-3-phenylquinoline-2,4-dicarbonitrile

(2,4-Dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol(100 mg, 0.2 mmol, Example 67), zinc cyanide (75 mg, 0.64 mmol), X-Phos(25 mg, 0.052 mmol), and Pd₂(dba)₃ (60 mg, 0.066 mmol) were all added toa large microwave vial. DMA (3 mL) was added and the vial was sealed andevacuated and the mixture was heated to 120° C. in an oil bath. After1.5 hours, the reaction mixture was filtered while still warm throughCelite® and rinsed with EtOAc. The effluent was concentrated and the DMAwas partially removed under high vacuum. The crude material waschromatographed on silica gel (3% MeOH-DCM increasing to 8% MeOH) whichprovided the title compound as a pale yellow foam. ¹H NMR (500 MHz,CDCl₃) δ 8.53 (s, 1H), 8.26 (d, J=8.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H),7.71-7.54 (m, 5H), 7.10 (s, 1H), 6.10 (s, 1H), 4.00 (s, 3H), 2.57 (s,3H), 2.14 (s, 3H); MS (ESI): mass calcd. for C₂₆H₁₉N₇OS, 477.1, m/zfound 478.1 [M+H]⁺.

The racemic mixture was separated by chiral chromatography using[Chiralcel OJ, 1000 A, 20 μM (Diacel), and 100% MeOH], to give twoenantiomers. The first eluting enantiomer was Example 47b and the secondeluting enantiomer was Example 47c.

Example 48[4-Chloro-2-(2-methoxyethoxy)-3-phenylquinolin-6-yl](4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), 2-methoxyethanol (16.0 μL, 0.202mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineraloil, 20.2 mg, 0.505 mmol) were combined in a round bottom flask under anN₂ atmosphere. The contents were heated to reflux and refluxedovernight. The reaction solution turned from a heterogeneous whitemixture to slightly yellowish with a moderate amount of precipitate. Thecontents were cooled to room temperature then transferred to aseparatory funnel with EtOAc dilution, and extracted with saturated,aqueous NH₄Cl and saturated, aqueous NaHCO₃ solutions. The organic phasewas separated then dried over MgSO₄, filtered and concentrated underreduced pressure. The crude product was purified by flash columnchromatography (silica gel, 0-10% DCM/(10% of a 2 M NH₃ MeOH in DCM))then further purified via reverse phase chromatography usingacetonitrile with ammonium hydroxide in water as eluent to afford thetitle compound. MS (ESI): mass calcd. for C₂₉H₂₅Cl₂N₃O₃, 533.1; m/zfound, 534.2 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.96 (d, J=0.9 Hz,1H), 8.19 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8,2.2 Hz, 1H), 7.48-7.44 (m, 4H), 7.43-7.39 (m, 3H), 7.36-7.33 (m, 2H),6.90 (d, J=1.6 Hz, 1H), 4.59-4.54 (m, 2H), 3.70 (s, 3H), 3.68-3.63 (m,2H), 3.25 (s, 3H).

Example 49a(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), toluene (2 mL), and sodium methoxide(109 mg, 2.02 mmol) were combined in a round bottom flask equipped witha stirbar and condenser under an N₂ atmosphere. The reaction solutionwas heated to reflux and refluxed overnight. Analysis showed anincomplete reaction, so additional sodium methoxide (109 mg, 2.02 mmol)was added and contents were refluxed for an additional day. The reactionwas cooled to room temperature and contents were transferred to aseparatory funnel with EtOAc dilution, and extracted with saturated,aqueous NH₄Cl then saturated, aqueous NaHCO₃ solutions. The organicphase was separated, dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified via reverse phasechromatography using acetonitrile with 0.05% trifluoroacetic acid inwater as eluent. The fractions from the purification containing thedesired product were lyophilized to provide the title compound as atrifluoroacetate salt. MS (ESI): mass calcd. for C₂₇H₂₁Cl₂N₃O₂, 489.1;m/z found, 490.1 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.97 (d, J=0.9Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.71 (dd,J=8.8, 2.2 Hz, 1H), 7.48-7.44 (m, 4H), 7.43-7.40 (m, 3H), 7.32-7.28 (m,2H), 6.90 (d, J=1.6 Hz, 1H), 3.98 (s, 3H), 3.70 (s, 3H).

(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFAwas purified on a chiralcel AD column (8 cm) with ethanol to provide twoenantiomers. The first eluting enantiomer was Example 49b: MS (ESI):mass calcd. for C₂₇H₂₁Cl₂N₃O₂, 489.1; m/z found, 490.2 [M+H]⁺; ¹H NMR(600 MHz, CD₃OD) δ ppm 8.14 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.87 (d,J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.1 Hz, 1H), 7.45 (dd, J=11.4, 4.4 Hz,2H), 7.42-7.34 (m, 5H), 7.33-7.27 (m, 2H), 6.40 (s, 1H), 3.97 (s, 3H),3.51 (s, 3H) and the second eluting enantiomer was Example 49c: MS(ESI): mass calcd. for C₂₇H₂₁Cl₂N₃O₂, 489.1; m/z found, 490.1 [M+H]⁺; ¹HNMR (600 MHz, CD₃OD) δ ppm 8.20-8.14 (m, 2H), 7.88 (d, J=8.8 Hz, 1H),7.69 (dd, J=8.8, 2.1 Hz, 1H), 7.47-7.42 (m, 2H), 7.42-7.35 (m, 5H),7.31-7.27 (m, 2H), 6.51 (s, 1H), 3.96 (s, 3H), 3.55 (s, 3H).

Example 50{4-Chloro-2-[(2-methoxyethyl)(methyl)amino]-3-phenylquinolin-6-yl}(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), N-(2-methoxymethyl)methylamine (900μL, 10.1 mmol), and methanol (2 mL) were combined in a reaction tube,which was then sealed and heated to 100° C. for 72 hours. The contentswere then cooled to room temperature, transferred to a round bottomflask and the solvent was removed via reduced pressure distillation. Thecrude residue was then taken up into EtOAc, transferred to a separatoryfunnel, extracted twice with a saturated, aqueous NH₄Cl solution. Theorganic phase was separated, dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash columnchromatography (silica gel, 0-10% DCM/(10% of a 2 M NH₃ MeOH in DCM))then further purified via reverse phase chromatography usingacetonitrile with 0.05% trifluoroacetic acid in water as eluent. Thefractions from the purification containing the desired product weretransferred to a separatory funnel with EtOAc and extracted with asaturated, aqueous NaHCO₃ solution. The aqueous layer was separated,extracted with EtOAc, then the combined organic phases were dried overMgSO₄, filtered and concentrated under reduced pressure to afford thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₈Cl₂N₄O₂, 546.2; m/zfound, 547.3 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.05 (d, J=2.0 Hz,1H), 7.97 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.1 Hz, 1H),7.45 (dd, J=10.3, 4.6 Hz, 2H), 7.38 (ddd, J=8.6, 4.5, 1.2 Hz, 1H),7.36-7.31 (m, 6H), 6.42 (s, 1H), 3.51 (s, 3H), 3.31-3.28 (m, 2H), 3.24(dd, J=8.7, 3.0 Hz, 2H), 3.17 (s, 3H), 2.74 (s, 3H).

Example 51N-[2-({4-Chloro-6-[(4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]-3-phenylquinolin-2-yl}oxy)ethyl]propanamide

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65), N-(2-hydroxylethyl)propionamide (34.2μL, 0.303 mmol), toluene (2 mL), and sodium hydride (60% dispersion inmineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flaskunder an N₂ atmosphere. The reaction solution was heated to reflux andrefluxed overnight. The reaction solution was cooled to room temperaturethen transferred to a separatory funnel with EtOAc dilution, andextracted with saturated, aqueous NH₄Cl then saturated, aqueous NaHCO₃solutions. The organic phase was separated, then dried over MgSO₄,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography (silica gel, 0-10% DCM/MeOH)then via reverse phase chromatography using acetonitrile with 0.05%trifluoroacetic acid in water as eluent. The fractions from thepurification containing the desired product were transferred to aseparatory funnel with EtOAc and extracted with a saturated, aqueousNaHCO₃ solution. The aqueous layer was separated, extracted with EtOAc,then the combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure to provide the title compound. MS(ESI): mass calcd. for C₃₁H₂₈Cl₂N₄O₃, 574.2; m/z found, 575.2 [M+H]⁺; ¹HNMR (600 MHz, CD₃OD) δ ppm 8.14 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.78(s, 1H), 7.68 (dd, J=8.8, 1.7 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.37 (m,1H), 7.38-7.34 (m, 4H), 7.34-7.30 (m, 2H), 6.32 (s, 1H), 4.52 (t, J=5.6Hz, 2H), 3.53-3.44 (m, 5H), 2.11 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.6 Hz,3H).

Example 52[2-(2-Aminoethoxy)-4-chloro-3-phenylquinolin-6-yl](4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(100 mg, 0.202 mmol, Example 65),N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (49 mg, 0.30 mmol), toluene(2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg,0.808 mmol) were combined in a round bottom flask and heated at refluxfor 48 hours under an N₂ atmosphere. Analysis after overnight reactionshowed only partial conversion, so additionalN-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (33 mg, 0.21 mmol) andsodium hydride (60% dispersion in mineral oil, 25 mg, 1.03 mmol) wereadded and the vessel was resealed and heated at reflux for an additional48 hours. The reaction solution was then cooled to room temperature,diluted with EtOAc, transferred to a separatory funnel, and extractedwith saturated, aqueous NH₄Cl then saturated, aqueous NaHCO₃ solutions.The organic phase was separated then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified viareverse phase chromatography using acetonitrile with 0.05%trifluoroacetic acid in water as eluent. The fractions from thepurification containing the desired product were transferred to aseparatory funnel with EtOAc and extracted with a saturated, aqueousNaHCO₃ solution. The aqueous layer was separated, extracted with EtOAc,then the combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure to afford the title compound. MS(ESI): mass calcd. for C₂₈H₂₄Cl₂N₄O₂, 518.1; m/z found, 519.2 [M+H]⁺; ¹HNMR (600 MHz, CD₃OD) δ ppm 8.17 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz,1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.69 (s, 1H), 7.50-7.45 (m, 2H),7.44-7.40 (m, 1H), 7.39-7.33 (m, 6H), 6.26 (s, 1H), 4.67-4.60 (m, 2H),3.47 (s, 3H), 3.20 (t, J=5.3 Hz, 2H).

Example 53{4-Chloro-2-[(2-methoxyethyl)(methyl)amino]-3-phenylquinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66),N-(2-methoxymethyl)methylamine (842 μL, 9.45 mmol), and methanol (2 mL)were combined in a reaction tube, which was then sealed and heated to100° C. for 48 hours. The contents were then cooled to room temperature,transferred to a round bottom flask and the solvent was removed viareduced pressure distillation. The crude residue was then taken up intoEtOAc, transferred to a separatory funnel and extracted twice with asaturated, aqueous NH₄Cl solution. The organic phase was separated,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude product was purified via reverse phase chromatography usingacetonitrile with 0.05% trifluoroacetic acid in water as eluent. Thefractions from the purification containing the desired product weretransferred to a separatory funnel with EtOAc and extracted with asaturated, aqueous NaHCO₃ solution. The aqueous layer was separated,extracted with EtOAc, then the combined organic phases were dried overMgSO₄, filtered and concentrated under reduced pressure to afford thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₇ClF₃N₅O₂, 581.2; m/zfound, 582.2 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.77 (d, J=1.8 Hz,1H), 8.08 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2, 1.9 Hz, 1H), 7.92 (s, 1H),7.84 (d, J=8.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.61 (dd, J=8.8, 2.1 Hz,1H), 7.49 (t, J=7.5 Hz, 2H), 7.42 (ddd, J=6.7, 2.5, 1.2 Hz, 1H),7.39-7.35 (m, 2H), 6.44 (s, 1H), 3.52 (s, 3H), 3.35-3.32 (m, 2H),3.30-3.27 (m, 2H), 3.19 (s, 3H), 2.78 (s, 3H).

Example 54[4-Chloro-3-phenyl-2-(2,2,2-trifluoroethoxy)quinolin-6-yl](1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66),2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol), toluene (2 mL), and sodiumhydride (60% dispersion in mineral oil, 19 mg, 0.47 mmol) were combinedin a round bottom flask under an N₂ atmosphere. The reaction solutionwas heated to reflux and refluxed overnight. Analysis showed thereaction had only progressed a moderate amount, so additional reagentswere added, 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol) and sodiumhydride (60% dispersion in mineral oil, 6 mg, 0.19 mmol) and contentswere heated at reflux for an additional 48 hours. The contents werecooled to room temperature then transferred to a separatory funnel withEtOAc dilution, and extracted with saturated, aqueous NH₄Cl thensaturated, aqueous NaHCO₃ solutions. The organic phase was separatedthen dried over MgSO₄, filtered and concentrated under reduced pressure.The crude material was purified via reverse phase chromatography usingacetonitrile with 0.05% trifluoroacetic acid in water as eluent. Thefractions from the purification containing the desired product weretransferred to a separatory funnel with EtOAc and extracted with asaturated, aqueous NaHCO₃ solution. The aqueous layer was separated,extracted with EtOAc, then the combined organic phases were dried overMgSO₄, filtered and concentrated under reduced pressure to afford thetitle compound. MS (ESI): mass calcd. for C₂₈H₁₉ClF₆N₄O₂, 592.1; m/zfound, 593.2 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.80 (d, J=2.1 Hz,1H), 8.28 (d, J=1.9 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H),7.97 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.3, 0.4 Hz, 1H), 7.75 (dd, J=8.8,2.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.34 (m, 2H), 6.60 (s, 1H), 5.00(q, J=8.6 Hz, 2H), 3.56 (s, 3H).

Example 55(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol

6-Bromo-2,4-dichloro-3-phenylquinoline (0.895 g, 2.54 mmol, Intermediate7: step c) and (1-methyl-1H-imidazol-5-yl)(pyrimidin-2-yl)methanone (500mg, 2.66 mmol, Intermediate 15: step b) were dissolved in THF (250 mL)in a dry round bottom flask under an N₂ atmosphere, then cooled to −78°C. in dry ice acetone bath. n-BuLi (2.5 M in hexanes, 0.966 mL, 2.42mmol) was then added dropwise via syringe over approximately 2 minutes.The reaction contents were stirred at −78° C. for approximately 1.5hours, then the dry ice bath was removed and allowed to warm to roomtemperature and stir for approximately 1 hour. The reaction was thenre-cooled to 0° C. and quenched with a saturated, aqueous NH₄Clsolution, then transferred to a separatory funnel with EtOAc. Theorganic phase was separated, then the aqueous layer was back extractedwith EtOAc, then the combined organic phases were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude product waspurified by flash column chromatography (silica gel, 0-10% DCM/(10% of a2M NH₃ MeOH in DCM)) then further purified via reverse phasechromatography using acetonitrile with 0.05% trifluoroacetic acid inwater as eluent. The fractions from the purification containing thedesired product were transferred to a separatory funnel with EtOAc andextracted with a saturated, aqueous NaHCO₃ solution. The aqueous layerwas separated, extracted with EtOAc, then the combined organic phaseswere dried over MgSO₄, filtered and concentrated under reduced pressureto afford the title compound. MS (ESI): mass calcd. for C₂₄H₁₇Cl₂N₅O,461.1; m/z found, 462.1 [M+H]⁺; ¹H NMR (600 MHz, CD₃OD) δ ppm 8.88 (d,J=4.9 Hz, 2H), 8.57 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.9, 2.0 Hz, 1H),7.99 (d, J=8.9 Hz, 1H), 7.80 (s, 1H), 7.54-7.45 (m, 4H), 7.36-7.32 (m,2H), 6.49 (d, J=1.0 Hz, 1H), 3.43 (s, 3H).

Example 56{4-Chloro-2-[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol(200 mg, 0.378 mmol, Example 66), N,O-dimethylhydroxylaminehydrochloride (376 mg, 3.78 mmol), and dimethylformamide (2 mL) werecombined in a reaction tube which was then sealed and heated to 100° C.for 48 hours. Analysis shows desired product, but also the presence ofstarting material. Additional N,O-dimethylhydroxylamine hydrochloride(190 mg, 0.195 mmol) was added and the contents were heated for anadditional 24 hours. The contents were then cooled, transferred to aseparatory funnel, diluted with EtOAc and extracted with a saturated,aqueous NH₄Cl solution, followed by deionized water (4×). The organicphase was separated, dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified via reverse phasechromatography using acetonitrile with ammonium hydroxide in water aseluent to afford the title compound. MS (ESI): mass calcd. forC₂₈H₂₃ClF₃N₅O₂, 553.1; m/z found, 554.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD)δ ppm 8.79 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2,1.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.75-7.68(m, 2H), 7.48 (t, J=7.4 Hz, 2H), 7.40 (ddd, J=7.4, 3.9, 1.3 Hz, 1H),7.32-7.24 (m, 2H), 6.35 (s, 1H), 3.48 (s, 3H), 3.07 (s, 3H), 2.77 (s,3H).

Example 57{2,4-Bis[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol

Purification of the crude product from the synthesis of{4-chloro-2-[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol(Example 56) also provided the title compound. MS (ESI): mass calcd. forC₃₀H₂₉F₃N₆O₃, 578.2; m/z found, 579.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δppm 8.75 (d, J=2.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.3, 1.8Hz, 1H), 7.97 (d, J=8.9 Hz, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.78-7.70 (m,2H), 7.44-7.37 (m, 2H), 7.36-7.29 (m, 1H), 7.24 (d, J=7.3 Hz, 2H), 6.33(s, 1H), 3.50 (s, 3H), 3.26 (s, 3H), 3.02 (s, 3H), 2.86 (s, 3H), 2.78(s, 3H).

Example 58{4-Chloro-2-[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(250 mg, 0.505 mmol, Example 65), N,O-dimethylhydroxylaminehydrochloride (1.01 g, 10.1 mmol), and dimethylformamide (2 mL) werecombined in a reaction tube, which was then sealed and heated to 100° C.for 48 hours. The contents were then cooled, transferred to a separatoryfunnel, diluted with EtOAc and extracted with saturated, aqueous NH₄Clsolution, followed by deionized water (4×). The organic phase wasseparated and dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified via reverse phasechromatography using acetonitrile with ammonium hydroxide in water aseluent to afford the title compound. MS (ESI): mass calcd. forC₂₈H₂₄Cl₂N₄O₂, 518.1; m/z found, 519.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δppm 8.14 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.1Hz, 1H), 7.67 (s, 1H), 7.47 (dd, J=11.4, 4.3 Hz, 2H), 7.39 (dt, J=4.4,1.8 Hz, 1H), 7.36 (d, J=4.1 Hz, 4H), 7.26 (dd, J=8.2, 1.3 Hz, 2H), 6.28(s, 1H), 3.46 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H).

Example 59{2,4-Bis[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

Purification of the crude product from the synthesis of{4-chloro-2-[methoxy(methyl)amino]-3-phenylquinolin-6-yl}(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol(Example 58) also provided the title compound. MS (ESI): mass calcd. forC₃₀H₃₀ClN₅O₃, 543.2; m/z found, 544.3 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δppm 8.36 (d, J=1.8 Hz, 1H), 7.96-7.89 (m, 1H), 7.71 (dd, J=8.9, 2.2 Hz,1H), 7.66 (s, 1H), 7.42-7.28 (m, 7H), 7.24 (d, J=6.6 Hz, 2H), 6.28 (d,J=1.0 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 3.01 (s, 3H), 2.85 (s, 3H),2.79 (s, 3H).

Example 60a(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol

(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol(156 mg, 0.337 mmol, Example 55), toluene (2 mL), and sodium methoxide(365 mg, 6.75 mmol) were combined in a round bottom flask equipped witha stirbar and condenser under an N₂ atmosphere. The contents were heatedto reflux and refluxed overnight. The reaction was cooled and thecontents were transferred to a separatory funnel with EtOAc dilution,and extracted with saturated, aqueous NH₄Cl then saturated, aqueousNaHCO₃ solutions. The organic phase was separated, dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material waspurified via reverse phase chromatography using acetonitrile with 0.05%trifluoroacetic acid in water as eluent. The fractions from thepurification containing the desired product were transferred to aseparatory funnel with EtOAc and extracted with a saturated, aqueousNaHCO₃ solution. The aqueous layer was separated, extracted with EtOAc,then the combined organic phases were dried over MgSO₄, filtered andconcentrated under reduced pressure to provide the title compound. MS(ESI): mass calcd. for C₂₅H₂₀ClN₅O₂, 457.1; m/z found, 458.2 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 8.81 (d, J=4.9 Hz, 2H), 8.48 (d, J=1.8 Hz,1H), 7.92-7.81 (m, 2H), 7.54-7.39 (m, 4H), 7.36-7.28 (m, 3H), 6.55 (s,1H), 6.15 (s, 1H), 3.98 (s, 3H), 3.40 (s, 3H).

(4-Chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanolwas purified on a chiralcel OD column (20 μm, Diacel) with methanol toprovide two enantiomers. The first eluting enantiomer was Example 60b:MS (ESI): mass calcd. for C₂₅H₂₀ClN₅O₂, 457.1; m/z found, 458.2 [M+H]⁺;¹H NMR (600 MHz, CD₃OD) δ ppm 8.86 (d, J=4.9 Hz, 2H), 8.41 (d, J=2.0 Hz,1H), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.63 (s, 1H),7.46-7.41 (m, 3H), 7.41-7.37 (m, 1H), 7.29 (d, J=7.0 Hz, 2H), 6.41 (s,1H), 3.95 (s, 3H), 3.39 (s, 3H).

Example 61(4-Chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.TFA

The title compound was prepared using(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (Intermediate 12:step b) in place of tert-butyl 4-nicotinoylpiperidine-1-carboxylateusing the procedure described for Example 69. ¹H NMR (400 MHz, CD₃OD) δ8.97 (s, 1H), 8.58-8.65 (m, 2H), 8.28 (d, J=9.09 Hz, 1H), 8.11 (dd,J=2.02, 9.09 Hz, 1H), 7.88-7.97 (m, 1H), 7.80 (d, J=7.58 Hz, 1H),7.48-7.55 (m, 3H), 7.38-7.46 (m, 1H), 7.26-7.34 (m, 2H), 7.11 (s, 1H),3.63 (s, 3H); MS m/e 495.3 [M+H]⁺.

Example 62(4-Chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol.TFA

A mixture of 6-bromo-4-chloro-3-phenyl-2-(trifluoromethyl)quinoline (864mg, 2.23 mmol, Intermediate 19: step b),(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (490 mg, 2.22 mmol,Intermediate 8: step b) and 22 mL of THF was purged with N₂ and cooledto −78° C. To the mixture was added n-BuLi (1.6 M in hexanes, 1.8 mL,2.9 mmol) dropwise and the color changed to orange then almost black.The reaction mixture was stirred at −78° C. to 0° C. for 70 minutes,then allowed to warm up to room temperature overnight. Saturated NH₄Cl(aqueous) was added and the organic layer was separated. The aqueouslayer was extracted with dichloromethane. The combined organic phaseswere dried (Na₂SO₄), filtered, and concentrated. The crude was purifiedby flash column chromatography (silica gel, 5-10% MeOH in DCM) followedby reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the titlecompound as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 8.42(d, J=2.02 Hz, 1H), 8.31 (d, J=8.59 Hz, 1H), 7.97 (dd, J=2.02, 9.09 Hz,1H), 7.47-7.54 (m, 4H), 7.41-7.47 (m, 3H), 7.27-7.34 (m, 2H), 6.99 (d,J=1.52 Hz, 1H), 3.71 (s, 3H); MS m/e 528.2 [M+H]⁺.

Example 63(4-Chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol

n-Butyllithium (2.0 mL, 3.202 mmol) was added to a −78° C. mixture of6-bromo-4-chloro-2-methoxy-8-methyl-3-(4-(trifluoromethoxy)phenyl)quinoline(1.1 g, 2.463 mmol, Intermediate 13: step d) and(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(0.691 g, 2.709 mmol, Intermediate 2: step c) in dry THF (25 mL) over a2 minute period. After complete addition stirring was continued at −78°C. for 10 minutes then the reaction was warmed up to 0° C. and stirredfor 1 hour. Saturated aqueous NH₄Cl was added and the reaction mixtureslowly warmed to room temperature. Water was added and the layers wereseparated. The aqueous layer was extracted with EtOAc. The combinedorganic extracts were dried (Na₂SO₄), filtered, evaporated in vacuo andchromatographed (DCM/10% MeOH in EtOAc) to provide the product. Furtherpurification using reverse phase HPLC (acetonitrile/water+0.1% TFA)provided the title compound. MS (ESI) 623.1 (M+H)⁺.

Example 64(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

A solution of n-BuLi (2.5 M in hexanes, 0.34 mL, 0.85 mmol) was addeddropwise by syringe to a solution of6-bromo-2,4-dichloro-3-phenylquinoline (305.4 mg, 0.865 mmol,Intermediate 7: step c) in dry THF (4.4 mL) at −78° C. After 1.5minutes, a solution of(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.175 g, 0.936 mmol,Intermediate 12: step b) in dry THF (1.8 mL) was added dropwise. Thereaction mixture was stirred for 5 minutes at −78° C., then the reactionflask was placed into an ice-water bath. After 10 minutes, the mixturewas warmed to room temperature and the reaction was quenched withmethanol and water. The mixture was partitioned between water and DCM.The separated aqueous phase was further extracted with DCM. The organicphase was dried (Na₂SO₄), filtered, and concentrated. The crude productwas purified by flash column chromatography (silica gel, 0-10% MeOH-DCM)to provide the title compound as a white solid. ¹H NMR (500 MHz, CDCl₃)δ 8.65 (ddd, J=4.9, 1.6, 1.0 Hz, 1H), 8.30 (d, J=1.7 Hz, 1H), 8.06 (d,J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 2.0 Hz, 1H), 7.73 (td, J=7.7, 1.7 Hz,1H), 7.55-7.47 (m, 4H), 7.36-7.29 (m, 3H), 7.23 (d, J=8.0 Hz, 1H), 6.37(d, J=1.1 Hz, 1H), 3.44 (s, 3H); MS m/e 461.1 [M+H]⁺.

Example 65(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-M-imidazol-5-yl)methanol

To (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (830 mg, 3.76mmol, Intermediate 8: step b) under an atmosphere of nitrogen was addedTHF (30 mL) and the mixture was heated until a solution was obtained. To6-bromo-2,4-dichloro-3-phenylquinoline (1.21 g, 3.42 mmol, Intermediate7: step c) under an atmosphere of nitrogen was added THF (25 mL). Theresulting colorless solution was cooled in a dry ice/acetone bath.n-BuLi (1.6 M in hexane, 2.35 mL, 3.76 mmol) was added dropwise. Themixture was stirred for 5 minutes before addition of the THF solution of(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone via cannula. Thereaction mixture was stirred in the dry ice/acetone bath for 30 minutes,then in an ice bath for 50 minutes and at room temperature for 15minutes, then was quenched by addition of saturated, aqueous NH₄Clsolution. The mixture was diluted with water and extracted three timeswith EtOAc. The organic phase was dried (Na₂SO₄), filtered, andconcentrated and the residue was purified by flash column chromatography(silica gel, 0-4% MeOH-DCM) to afford the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 8.32 (d, J=1.96 Hz, 1H), 8.02 (d, J=8.80 Hz, 1H), 7.72(dd, J=2.20, 8.80 Hz, 1H), 7.48-7.56 (m, 3H), 7.30-7.38 (m, 7H), 6.40(d, J=1.22 Hz, 1H), 3.39 (s, 3H); MS m/e 494.1 (M+H)⁺.

Example 66(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methanol.TFA

(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone(3.00 g, 8.50 mmol, Intermediate 2: step c) and6-bromo-2,4-dichloro-3-phenylquinoline (2.32 g, 9.08 mmol, Intermediate7: step c) were dissolved in THF (250 mL) under an N₂ atmosphere in adry round bottom flask, then cooled to −78° C. in dry ice/acetone bath.n-BuLi (2.5 M in hexanes, 3.24 mL, 8.09 mmol) was then added dropwisevia syringe over approximately 2 minutes. The contents were stirred at−78° C. for approximately 2.5 hours, then the dry ice bath was removedand the contents were allowed to warm to room temperature. The reactionwas then cooled to 0° C. in an ice water bath and quenched with asaturated, aqueous NH₄Cl solution, then transferred to a separatoryfunnel with EtOAc dilution. The organic phase was separated, then theaqueous layer was back extracted twice with EtOAc, then the combinedorganic phases were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude product was purified by RP-HPLC (40-80%CH₃CN—H₂O, 0.1% TFA) to afford the title compound as a yellow solid. MS(ESI): mass calcd. for C₂₆H₁₇Cl₂F₃N₄O, 528.1; m/z found, 529.4 [M+H]⁺;¹H NMR (600 MHz, CD₃OD) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.35 (d, J=1.8 Hz,1H), 8.07-8.03 (m, 2H), 7.88 (dd, J=8.9, 2.1 Hz, 1H), 7.85 (d, J=8.3 Hz,1H), 7.76 (s, 1H), 7.54-7.50 (m, 3H), 7.37-7.33 (m, 2H), 6.39 (d, J=1.1Hz, 1H), 3.48 (s, 3H).

Example 67(2,4-Dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (750 mg,2.12 mmol, Intermediate 7: step c) was added THF (30 mL) to give ahomogeneous clear solution. The solution was cooled in a dry ice bathand n-BuLi (2.5 M in hexanes, 0.840 mL, 2.1 mmol) was introduced. After2 minutes, a solution of(2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (600mg, 2.7 mmol, Intermediate 16: step b) in 18 mL THF was added. Thedry-ice bath was replaced with a 0° C. ice-bath and after 45 minutes thereaction mixture was quenched with NH₄Cl solution and the aqueousportion was extracted with EtOAc (4×50 mL). The combined organics werewashed with brine, dried over MgSO₄, filtered and concentrated. Thecrude material was triturated with Et₂O to afford the title compound asa light tan solid. The mother liquors were chromatographed on silica gel(2% MeOH/DCM increasing to 5% MeOH) which provided additional titlecompound. ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J=2.0 Hz, 1H), 8.09 (d,J=8.9 Hz, 1H), 7.73 (dd, J=8.9, 2.2 Hz, 1H), 7.58-7.46 (m, 3H),7.20-7.33 (m, 2H), 7.20 (s, 1H), 4.38 (s, 1H), 3.94 (s, 3H), 2.58 (s,3H), 2.16 (s, 3H); MS (ESI); mass calcd. for C₂₄H₁₉Cl₂N₅OS, 495.1, m/zfound 496.1 [M+H]⁺.

Example 68(2,4-Dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanol

To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (450 mg,1.27 mmol, Intermediate 7: step c) was added THF (15 mL) to give ahomogeneous clear solution. The solution was cooled in a dry ice bathand n-BuLi (2.5 M in hexanes, 0.45 mL, 1.13 mmol) was added. After 2minutes, a solution of(2,4-dimethylthiazol-5-yl)(1-methyl-1H-imidazol-5-yl)methanone (350 mg,1.58 mmol, Intermediate 17: step b) in 4 mL THF was introduced. Thedry-ice bath was replaced with a 0° C. bath and after 35 minutes thereaction mixture was quenched with aqueous NH₄Cl solution and theaqueous portion was extracted with EtOAc (4×50 mL). The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated. Chromatography on silica gel (20% acetone-DCM increasingto 5% MeOH-DCM) afforded the title compound as a pale yellowish solid.¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J=1.9 Hz, 1H), 8.03 (d, J=8.8 Hz,1H), 7.79 (dd, J=8.8, 2.1 Hz, 1H), 7.59-7.41 (m, 3H), 7.40-7.31 (m, 2H),7.28 (d, J=6.4 Hz, 1H), 6.44 (s, 1H), 5.46 (s, 1H), 3.48 (s, 3H), 2.56(s, 3H), 2.13 (s, 3H); MS (ESI): mass calcd. for C₂₅H₂₀Cl₂N₄OS, 494.1,m/z found 495.0 [M+H]⁺.

Example 69 tert-Butyl4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate

To a solution of 4-chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline(Intermediate 20: step b, containing about 13% molar of4-chloro-3-phenyl-2-(trifluoromethyl)quinoline as impurity, 340 mg) inTHF (4 mL) at −78° C. under N₂ was added iPrMgCl (2.0 M in THF, 0.40 mL,0.8 mmol). After stirring for 8 minutes, the cooling bath was removed,and stirring was continued for 20 minutes, then tert-butyl4-nicotinoylpiperidine-1-carboxylate (225 mg, 0.770 mmol, Intermediate21) was added in neat. After stirring at room temperature overnight, themixture became clear brown and was heated at 50° C. for 1.5 hours. Themixture was quenched with saturated NH₄Cl aqueous solution, andextracted with EtOAc. The extracts were dried over Na₂SO₄, filtered, andconcentrated. The crude mixture was purified by flash columnchromatography (silica gel, 20-100% EtOAc in heptanes) to provide thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 9.17-9.35 (m, 1H), 8.50-8.88(m, 2H), 8.29 (d, J=7.58 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 7.82-8.00 (m,1H), 7.47-7.57 (m, 4H), 7.21-7.33 (m, 2H), 4.08-4.26 (m, 2H), 2.69-2.99(m, 3H), 1.82-1.92 (m, 1H), 1.53-1.80 (m, 3H), 1.47 (s, 4.5H), 1.41 (s,4.5H); MS m/e 598.3 [M+H]⁺.

Example 70(4-Chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(piperidin-4-yl)(pyridin-3-yl)methanol

A solution of tert-butyl4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate(313 mg, 0.520 mmol, Example 69) in DCM (6 mL) was treated with 1.8 mLof TFA, stirred for 3 hours, and concentrated. The residue waspartitioned between saturated NaHCO₃ aqueous solution and DCM. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to drynessto provide the title compound as a light brown solid. ¹H NMR (400 MHz,CDCl₃) δ 8.86 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=4.55 Hz, 1H), 8.21 (d,J=9.09 Hz, 1H), 7.89-7.96 (m, 2H), 7.46-7.53 (m, 4H), 7.23-7.32 (m, 2H),3.23-3.36 (m, 2H), 2.77-2.91 (m, 3H), 1.66-1.86 (m, 4H).

Example 714-Chloro-6-((4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-N,N-dimethyl-3-phenylquinolin-2-amine

To(4-chloro-2-(dimethylamino)-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol(83.6 mg, 0.166 mmol, Example 90) in NMP (1.5 mL), was added copper (I)cyanide (16.4 mg, 0.183 mmol). The mixture was heated by microwaveirradiation for 10 minutes at 120° C. The mixture was partitionedbetween MTBE and saturated aqueous NH₄OH. The organic phase was washedwith water. The organic phase was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by RP-HPLC (10-90%CH₃CN—H₂O, 0.1% TFA) and fractions were converted to the correspondingfree base by extraction from saturated aqueous NaHCO₃ with DCM. Furtherpurification by flash column chromatography (silica gel, 10-70%acetone-DCM) afforded the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.82(d, J=1.96 Hz, 1H), 7.76 (d, J=8.80 Hz, 1H), 7.55 (br. s., 1H),7.43-7.50 (m, 2H), 7.34-7.42 (m, 4H), 7.30 (d, J=8.56 Hz, 2H), 7.12 (d,J=8.56 Hz, 2H), 6.48 (br. s., 1H), 5.45 (s, 1H), 3.37 (s, 3H), 2.71 (s,6H); MS m/e 487.0 (M+H)⁺.

Example 724-Chloro-6-((4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinoline-2-carbonitrile.TFA

Copper (I) cyanide (44.4 mg, 0.496 mmol) was added to a colorlesssolution of(4-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(123 mg, 0.248 mmol, Example 65) in NMP (1 mL). The mixture was stirreduntil CuCN dissolved, then was heated by microwave irradiation at 145°C. for 40 minutes. The mixture was partitioned between saturated aqueousNH₄OH and MTBE. The aqueous phase was extracted twice with MTBE. Theorganic phases were combined, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by RP-HPLC (10-90% CH₃CN—H₂O, 0.1%TFA) to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s,1H), 8.26 (d, J=8.80 Hz, 1H), 8.05 (d, J=1.96 Hz, 1H), 7.66 (dd, J=1.96,8.80 Hz, 1H), 7.52-7.62 (m, 3H), 7.37-7.49 (m, 4H), 7.12 (d, J=8.31 Hz,2H), 6.78 (s, 1H), 5.63 (s, 1H), 3.62 (s, 3H); MS m/e 469.0 (M+H)⁺.

Example 73(2,4-Dichloro-3-(2-chlorophenyl)quinolin-6-yl)(phenyl)(pyridin-4-yl)methanol

To a solution of 6-bromo-2,4-dichloro-3-(2-chlorophenyl)quinoline (387.5mg, 1 mmol, Intermediate 32: step c) in THF (15 mL) at −78° C. was addednBuLi (2.5 M in hexanes, 0.52 mL, 1.3 mmol) dropwise and the resultingmixture stirred at −78° C. for 15 minutes. Then,phenyl(pyridin-4-yl)methanone (183 mg, 1 mmol) was added, and theresulting mixture stirred at −78° C. for 15 minutes. The dry ice-acetonebath was then removed and the mixture was allowed to warm to roomtemperature over 2 hours. The reaction was quenched by the addition ofwater (10 mL) and then extracted with DCM (2×20 mL). The organics werecombined, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by FCC (1:20 MeOH/DCM) to provide the titlecompound. MS (ESI): mass calcd. for C₂₇H₁₇Cl₃N₂O, 490.0, m/z found 491.0[M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.54 (dd, J=4.7, 1.7 Hz, 2H),8.25-8.22 (m, 1H), 8.06-8.02 (m, 1H), 7.93-7.88 (m, 1H), 7.64-7.60 (m,1H), 7.57-7.52 (m, 1H), 7.52-7.50 (m, 1H), 7.50-7.47 (m, 2H), 7.42-7.33(m, 6H).

Example 74(2,4-Dichloro-3-(2-chlorophenyl)quinolin-6-yl)(oxazol-2-yl)(phenyl)methanol

To a solution of 6-bromo-2,4-dichloro-3-(2-chlorophenyl)quinoline (387.5mg, 1 mmol, Intermediate 32: step c) in THF (15 mL) at −78° C. was addednBuLi (2.5 M in hexanes, 0.52 mL, 1.3 mmol) dropwise and the resultingmixture stirred at −78° C. for 15 minutes. Then,phenyl(pyridin-4-yl)methanone (183 mg, 1 mmol) was added, and theresulting mixture stirred at −78° C. for 15 minutes. The dry ice-acetonebath was then removed and the mixture was allowed to warm to roomtemperature over 2 hours. The reaction was quenched by the addition ofwater (10 mL) and then extracted with DCM (2×20 mL). The organics werecombined, dried (MgSO₄), filtered and concentrated to dryness. Theresidue was purified by FCC (1:5 EtOAc/petroleum ether) to provide thetitle compound. MS (ESI): mass calcd. for C₂₅H₁₅Cl₃N₂O₂, 480.0, m/zfound 481.0 [M+H]⁺. ¹H NMR (300 MHz, CD₃OD) δ 8.34 (d, J=1.8 Hz, 1H),8.03-7.89 (m, 3H), 7.64-7.57 (m, 1H), 7.56-7.44 (m, 2H), 7.42-7.29 (m,6H), 7.23 (s, 1H).

Example 756-((3-Chlorophenyl)(hydroxy)(6-(trifluoromethyl)pyridin-3-yl)methyl)-3-phenylquinoline-2-carbonitrile

A pressure tube containing(3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(94 mg, 0.17 mmol, Intermediate 22: step b), Pd₂(dba)₃ (8.0 mg, 0.0087mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf, 10 mg, 0.018 mmol),zinc cyanide (25 mg, 0.21 mmol), and zinc nanopowder (3.0 mg, 0.046mmol) in N,N-dimethylacetamide (1 mL) was sparged with nitrogen for 5minutes, and then heated at 120° C. for 1 hour followed by 100° C. for 3hours. The mixture was allowed to cool to room temperature and filteredthrough a syringe filter. The filtrate was concentrated in vacuo, thenEtOAc and NH₄OH (aqueous) were added. The organic layer was separated,and the aqueous layer was extracted with EtOAc. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash column chromatography (silica gel column, 30-50% EtOAcin heptane), and then by reverse phase HPLC (water/acetonitrile/0.1%TFA) to provide the title compound as a by-product. ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=2.02 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J=9.60 Hz, 1H),7.93 (dd, J=2.02, 8.08 Hz, 1H), 7.75-7.79 (m, 2H), 7.71 (d, J=8.08 Hz1H), 7.60-7.65 (m, 2H), 7.51-7.58 (m, 3H), 7.32-7.40 (m, 3H), 7.15 (dt,J=1.52, 7.58 Hz, 1H).

Example 766-((3-Chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2,4-dicarbonitrile

The title compound was prepared using(3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(2-(trifluoromethyl)pyridin-4-yl)methanol(Example 77) in place of(3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol(Intermediate 22: step b) according to the procedure described inExample 75. ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=5.56 Hz, 1H), 8.46 (d,J=1.52 Hz, 1H), 8.31 (d, J=9.09 Hz, 1H), 7.90 (d, J=1.52 Hz, 1H), 7.84(dd, J=2.02, 8.59 Hz, 1H), 7.60-7.67 (m, 5H), 7.58 (dd, J=1.52, 5.05 Hz,1H), 7.35-7.46 (m, 2H), 7.23-7.27 (m, 1H), 7.10 (dt, J=1.52, 8.08 Hz,1H).

Example 77(3-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(2-(trifluoromethyl)pyridin-4-yl)methanol

To a solution of 6-bromo-2,4-dichloro-3-phenylquinoline (286 mg, 0.810mmol, Intermediate 7: step c) and(3-chlorophenyl)(2-(trifluoromethyl)pyridin-4-yl)methanone (231 mg,0.810 mmol, Intermediate 23: step b) in THF (6 mL) at −78° C. was added1.6 M n-BuLi in hexane (0.76 mL, 1.22 mmol). The mixture was stirred at−78° C. to 10° C. for 2 hours and then quenched with NH₄Cl (aqueous).The organic layer was separated, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic phases were dried (Na₂SO₄), filtered,concentrated, and purified by flash column chromatography (40 g silicagel column, 10-40% EtOAc in heptane) to afford the title compound as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J=5.56 Hz, 1H), 8.23(d, J=2.53 Hz, 1H), 8.09 (d, J=9.09 Hz, 1H), 7.84 (d, J=1.52 Hz, 1H),7.68 (dd, J=2.02, 8.59 Hz, 1H), 7.46-7.56 (m, 4H), 7.30-7.40 (m, 4H),7.25-7.28 (m, 1H), 7.13 (dt, J=1.52, 7.58 Hz, 1H).

Example 78(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methylpiperidin-4-yl)(pyridin-3-yl)methanol.TFA

To a mixture of(2,4-dichloro-3-phenylquinolin-6-yl)(piperidin-4-yl)(pyridin-3-yl)methanol.TFA(15 mg, 0.022 mmol, Example 91), formaldehyde (0.010 mL, 0.13 mmol, 37%in water), and MeOH (1 mL) was added NaCNBH₃ (4.0 mg, 0.063 mmol). Afterstirring at room temperature overnight, the mixture was concentrated andpurified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to providethe title compound as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s,1H), 8.56-8.62 (m, 2H), 8.44 (d, J=8.31 Hz, 1H), 8.03 (s, 2H), 7.70-7.76(m, 1H), 7.47-7.57 (m, 3H), 7.33 (d, J=6.85 Hz, 2H), 3.50-3.60 (m, 2H),3.03-3.19 (m, 3H), 2.86 (s, 3H), 1.82-1.98 (m, 2H), 1.64-1.77 (m, 2H);MS m/e 478.0 [M+H]⁺.

Example 79(3-Chlorophenyl)(2-isopropoxy-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol.TFA

A mixture of(3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol(21 mg, 0.043 mmol, Intermediate 24) and NaOiPr (11 mg, 0.13 mmol) iniPrOH (0.4 mL) was heated in a sealed tube at 80° C. for 5 hours. MoreNaOiPr (15 mg, 0.18 mmol) was added and the mixture was heated at thesame temperature for 21 hours. After cooling to room temperature, themixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA)to provide the title compound as a by-product. ¹H NMR (400 MHz, CD₃OD) δ8.86 (s, 1H), 8.75-8.81 (m, 1H), 8.52 (d, J=8.31 Hz, 1H), 8.03 (s, 1H),7.97-8.03 (m, 1H), 7.82 (d, J=8.80 Hz, 1H), 7.65 (d, J=2.20 Hz, 1H),7.56-7.63 (m, 3H), 7.46-7.48 (m, 1H), 7.33-7.45 (m, 5H), 7.25-7.29 (m,1H), 5.59-5.66 (m, 1H), 1.38 (d, J=6.36 Hz, 6H).

Example 80(4-Butyl-2-isopropoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA

A mixture of(4-butyl-2-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA(16 mg, 0.023 mmol, Intermediate 26) and NaOiPr (19 mg, 0.23 mmol) iniPrOH (0.4 mL) was heated in a sealed tube at 80° C. for 17 hours. MoreNaOiPr (7.0 mg, 0.085 mmol) was added and the mixture was heated at thesame temperature for 64 hours. After cooling to room temperature, themixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA)to provide the title compound. ¹H NMR (400 MHz, CD₃OD) δ 9.06 (s, 1H),8.78 (d, J=6.57 Hz, 2H), 7.86-7.90 (m, 4H), 7.67 (dd, J=2.02, 9.09 Hz,1H), 7.36-7.47 (m, 3H), 7.16-7.20 (m, 2H), 7.12 (d, J=1.52 Hz, 1H),5.44-5.52 (m, 1H), 3.72 (s, 3H), 2.66-2.74 (m, 2H), 1.34-1.44 (m, 2H),1.22 (d, J=6.06 Hz, 6H), 1.12-1.19 (m, 2H), 0.73 (t, J=7.33 Hz, 3H); MSm/e 507.3 [M+H]⁺.

Example 81(3-Chlorophenyl)(2,4-diethoxy-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol.TFA

A mixture of(3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol(27 mg, 0.055 mmol, Intermediate 24) and NaOEt (0.30 mL, 3.8 mmol, 21%wt. in EtOH) was heated in a sealed tube at 82° C. for 24 hours. Aftercooling to room temperature, the mixture was purified by reverse phaseHPLC (water/acetonitrile/0.1% TFA) to provide the title compound. ¹H NMR(400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.81 (s, 1H), 8.55 (d, J=8.07 Hz, 1H),8.05 (br. s., 1H), 7.87 (s, 1H), 7.84 (d, J=8.80 Hz, 1H), 7.61 (d,J=7.09 Hz, 1H), 7.49 (s, 1H), 7.33-7.45 (m, 7H), 7.29 (br. s., 1H), 4.47(q, J=7.09 Hz, 2H), 3.51-3.63 (m, 2H), 1.30 (t, J=6.97 Hz, 3H), 0.95 (t,J=7.09 Hz, 3H).

Example 82(4-Chloro-2-(methyl(2-(methylamino)ethyl)amino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA

A mixture of(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA(18 mg, 0.026 mmol, Intermediate 25: step c) andN¹,N²-dimethylethane-1,2-diamine (500 mg, 5.67 mmol) was heated in asealed tube at 80° C. for 24 hours. After cooling to room temperature,the mixture was purified by reverse phase HPLC (water/acetonitrile/0.1%TFA) to provide the title compound. ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s,1H), 8.87 (br. s., 2H), 8.25 (d, J=2.02 Hz, 1H), 8.09 (d, J=6.57 Hz,2H), 7.90 (d, J=9.09 Hz, 1H), 7.72 (dd, J=2.02, 8.59 Hz, 1H), 7.49-7.59(m, 2H), 7.43-7.49 (m, 1H), 7.35-7.43 (m, 2H), 7.21 (d, J=1.52 Hz, 1H),3.76-3.88 (m, 2H), 3.70 (s, 3H), 3.22-3.29 (m, 2H), 2.76 (s, 3H), 2.51(s, 3H); MS m/e 513.0 [M+H]⁺.

Example 832-((4-Chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methyl)-3-phenylquinolin-2-yl)(methyl)amino)ethanol.TFA

A mixture of(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol.TFA(20 mg, 0.029 mmol, Intermediate 25: step c) and 2-(methylamino)ethanol(408 mg, 5.43 mmol) was heated in a sealed tube at 80° C. for 16 hours.After cooling to room temperature, the mixture was purified by reversephase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound.¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 8.81 (br. s., 2H), 8.37 (s, 1H),7.97 (d, J=6.06 Hz, 2H), 7.89 (s, 2H), 7.59-7.64 (m, 1H), 7.52-7.58 (m,2H), 7.42-7.47 (m, 2H), 7.21 (d, J=1.52 Hz, 1H), 3.81 (t, J=4.55 Hz,2H), 3.69 (s, 3H), 3.64 (t, J=4.55 Hz, 2H), 2.78 (s, 3H); MS m/e 500.0[M+H]⁺.

Example 84(4-Chloro-2-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol.TFA

A mixture of(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol.TFA(35 mg, 0.051 mmol, Intermediate 27) and dimethylamine (0.8 mL, 1.6mmol, 2.0 M in MeOH) was heated in a sealed tube at 80° C. for 4.5 days.After cooling to room temperature, the mixture was purified by reversephase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound.¹H NMR (400 MHz, CD₃OD) δ 8.81 (d, J=7.09 Hz, 2H), 8.57-8.61 (m, 1H),8.20-8.26 (m, 3H), 8.06 (d, J=8.80 Hz, 1H), 7.92-7.98 (m, 1H), 7.85-7.92(m, 2H), 7.50-7.61 (m, 3H), 7.37-7.47 (m, 3H), 3.00 (s, 6H).

Example 85(2-Chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.TFA

A mixture of(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol(28 mg, 0.41 mmol, Example 64) and dimethylamine (0.8 mL, 1.6 mmol, 2.0M in MeOH) was heated in a sealed tube at 80° C. for 4.5 days. Aftercooling to room temperature, the mixture was purified by reverse phaseHPLC (water/acetonitrile/0.1% TFA) to afford the title compound. ¹H NMR(400 MHz, CD₃OD) δ 8.94 (s, 1H), 8.59-8.64 (m, 1H), 8.18-8.20 (m, 1H),7.87-7.96 (m, 3H), 7.77 (d, J=8.07 Hz, 1H), 7.41-7.53 (m, 4H), 7.25-7.32(m, 2H), 7.03 (d, J=1.71 Hz, 1H), 3.64 (s, 3H), 2.69 (s, 6H); MS m/e470.0 [M+H]⁺.

Example 86(2,4-Dichloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol

The title compound was prepared using(2-fuoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanone (Intermediate28: step b) in place of(3-chlorophenyl)(2-(trifluoromethyl)pyridin-4-yl)methanone (Intermediate23: step b) according to the procedure described in Example 77. ¹H NMR(400 MHz, CDCl₃) δ 8.18 (d, J=1.96 Hz, 1H), 8.15 (d, J=5.38 Hz, 1H),8.05 (d, J=8.80 Hz, 1H), 7.73 (dd, J=2.20, 8.80 Hz, 1H), 7.49-7.53 (m,3H), 7.27-7.34 (m, 2H), 7.21 (dt, J=1.59, 5.38 Hz, 1H), 6.99 (s, 1H),6.91 (d, J=1.22 Hz, 1H), 6.88 (d, J=1.22 Hz, 1H), 3.39 (s, 3H); MS m/e478.8 [M+H]⁺.

Example 87(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(2,4-dimethylthiazol-5-yl)methanol

To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (255 mg,0.72 mmol, Intermediate 7: step c) was added THF (8 mL) to give ahomogeneous clear solution. The solution was cooled in a −78° C. bathand then n-BuLi (2.5 M in hexanes, 0.26 mL, 0.65 mmol) was added whichresulted in an immediate orange homogeneous solution. Afterapproximately 2 minutes,(4-chlorophenyl)(2,4-dimethylthiazol-5-yl)methanone (210 mg, 0.83 mmol,Intermediate 30, in 3 mL THF) was added. The reaction mixture wasmaintained at −75° C. for 5 minutes then replaced with a 0° C. ice-bath.After 45 minutes, the reaction mixture was quenched with aqueous NH₄Clsolution. The aqueous portion was extracted with EtOAc (3×50 mL) and thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated to dryness. Chromatography on silica gel (100% DCMincreasing to 20% EtOAc-DCM) provided the title compound as a whiteamorphous solid. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.33 (s, 1H), 8.01 (d, J=8.8Hz, 1H), 7.82 (dd, J=8.9, 2.1 Hz, 1H), 7.59-7.46 (m, 3H), 7.46-7.28 (m,6H), 2.54 (s, 3H), 2.03 (s, 3H). MS (ESI): mass calcd. forC₂₇H₁₉Cl₃N₂OS, 524.0, m/z found 525.0 [M+H]⁺.

Example 88(2,4-Dimethoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyrimidin-2-yl)methanol

Purification of the crude reaction mixture from the synthesis of(4-chloro-2-methoxy-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol(Example 60a) also afforded the title compound as a regioisomer. MS(ESI): mass calcd. for C₂₆H₂₃N₅O₃, 453.2; m/z found, 454.3 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.86 (d, J=4.9 Hz, 2H), 8.26 (d, J=1.7 Hz, 1H),7.86-7.75 (m, 3H), 7.47-7.36 (m, 6H), 6.52 (s, 1H), 3.95 (s, 3H), 3.48(s, 3H), 3.44 (s, 3H).

Example 89(2-Chloro-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

To a 50-mL round-bottom flask containing a solution of6-bromo-2-chloro-3-phenylquinoline (210 mg, 0.66 mmol, Intermediate 31:step b) in tetrahydrofuran (10 mL) was added 2.5 M n-BuLi in hexanes(0.29 mL, 0.72 mmol) dropwise with stirring at −78° C. After 45 minutesat −78° C., a solution of(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (132 mg, 0.60 mmol,Intermediate 8: step b) in tetrahydrofuran (2 mL) was added dropwise.The resulting solution was stirred at −78° C. for an additional 2 hours,then quenched with 30 mL of aqueous NH₄Cl and extracted with ethylacetate (2×30 mL). The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby FCC (20:1 DCM/MeOH) to provide the title compound as a white solid.MS (ES): mass calcd. for C₂₆H₁₉Cl₂N₃O, 459.1; m/z found, 460.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.96 (d, J=3.9 Hz, 1H), 8.33 (s, 1H), 8.05 (d,J=6.0 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.42-7.56 (m, 9H),6.93 (s, 1H), 3.71 (s, 3H).

Example 90(4-Chloro-2-(dimethylamino)-3-phenylquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol(124 mg, 0.251 mmol, Example 65) was treated with dimethylamine (2 M inMeOH, 2 mL, 4 mmol) and the resulting suspension was heated in a sealedtube in an 85° C. oil bath for 2 days. The mixture was concentrated invacuo and the residue was purified by flash column chromatography(Biotage NH column, 0-1% MeOH-DCM) to provide the title compound as acream-colored foam. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=2.20 Hz, 1H),7.72 (d, J=8.80 Hz, 1H), 7.43-7.52 (m, 3H), 7.34-7.43 (m, 3H), 7.22-7.34(m, 6H), 6.33 (s, 1H), 3.36 (s, 3H), 2.72 (s, 6H).

Example 91(2,4-Dichloro-3-phenylquinolin-6-yl)(piperidin-4-yl)(pyridin-3-yl)methanol.TFA

A solution of tert-butyl4-((2,4-dichloro-3-phenylquinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate(149 mg, 0.260 mmol, Intermediate 29) and TFA (1 mL) was stirred at roomtemperature for 1 hour and concentrated to provide the title compound.¹H NMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 8.69-8.77 (m, 2H), 8.62 (s, 1H),8.02-8.11 (m, 2H), 7.97 (dd, J=5.56, 8.08 Hz, 1H), 7.49-7.58 (m, 3H),7.30-7.36 (m, 2H), 3.40-3.50 (m, 2H), 3.17-3.27 (m, 1H), 3.05-3.17 (m,2H), 1.75-1.94 (m, 2H), 1.60-1.74 (m, 2H).

In Vitro Biological Data

ThermoFluor® Assay

ThermoFluor® is a fluorescence based assay that estimates ligand bindingaffinities by measuring the effect of a ligand on protein thermalstability (Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D.,Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P., and Salemme, F. R. (2001) High-density miniaturizedthermal shift assays as a general strategy for drug discovery. J BiomolScreen 6, 429-40, and Matulis, D., Kranz, J. K., Salemme, F. R., andTodd, M. J. (2005) Thermodynamic stability of carbonic anhydrase:measurements of binding affinity and stoichiometry using ThermoFluor.Biochemistry 44, 5258-66). This approach is applicable to a wide varietyof systems, and rigorous in theoretical interpretation throughquantitation of equilibrium binding constants (K_(D)).

In a ThermoFluor® experiment where protein stability is monitored as thetemperature is steadily increased, an equilibrium binding ligand causesthe midpoint of an unfolding transition (T_(m)) to occur at a highertemperature. The shift in the melting point described as a ΔT_(m) isproportional to the concentration and affinity of the ligand. Thecompound potency may be compared as a rank order of either ΔT_(m) valuesat a single compound concentration or in terms of K_(D) values,estimated from concentration response curves.

RORγt ThermoFluor® Assay Construct

For the RORγt construct used in the ThermoFluor® assay, numbering forthe nucleotide sequences was based on the reference sequence for humanRORγt, transcript variant 2, NCBI Accession: NM_001001523.1 (SEQ IDNO:1). Nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type humanRORγt ligand binding domain (RORγt LBD) were cloned into the pHIS1vector, a modified pET E. coli expression vector (Accelagen, San Diego),containing an in-frame N-terminal His-tag and a TurboTEV proteasecleavage site (ENLYFQG, SEQ ID NO:3) upstream of the cloned insertsequence. The amino acid sequence for the RORγt construct used in theThermofluor assay is shown as SEQ ID NO:4.

ThermoFluor® experiments were carried out using instruments owned byJanssen Research and Discovery, L.L.C. through its acquisition of3-Dimensional Pharmaceuticals, Inc. 1,8-ANS (Invitrogen) was used as afluorescent dye. Protein and compound solutions are dispensed into black384-well polypropylene PCR microplates (Abgene) and overlayed withsilicone oil (1 μL, Fluka, type DC 200) to prevent evaporation.

Bar-coded assay plates are robotically loaded onto a thermostaticallycontrolled PCR-type thermal block and then heated at a typical ramp-rateof 1° C./min for all experiments. Fluorescence was measured bycontinuous illumination with UV light (Hamamatsu LC6) supplied via fiberoptic and filtered through a band-pass filter (380-400 nm; >6 ODcutoff). Fluorescence emission of the entire 384-well plate was detectedby measuring light intensity using a CCD camera (Sensys, RoperScientific) filtered to detect 500±25 nm, resulting in simultaneous andindependent readings of all 384 wells. Images were collected at eachtemperature, and the sum of the pixel intensity in a given area of theassay plate was recorded versus temperature. Reference wells containedRORγt without compounds, and the assay conditions were as follows:

-   -   0.065 mg/mL RORγt    -   60 μM 1,8-ANS    -   100 mM Hepes, pH 7.0    -   10 mM NaCl    -   2.5 mM GSH    -   0.002% Tween-20

Project compounds were arranged in a pre-dosed mother plate (GreinerBio-one) wherein compounds are serially diluted in 100% DMSO by 1:2 froma high concentration of 10 mM over 12 columns within a series (column 12is a reference well containing DMSO, no compound). The compounds wererobotically dispensed directly into assay plates (1×=46 nL) using aHummingbird capillary liquid handling instrument (Digilab). Followingcompound dispense, protein and dye in buffer was added to achieve thefinal assay volume of 3 μL, followed by 1 μL of silicone oil.

The binding affinity was estimated as described previously (Matulis, D.,Kranz, J. K., Salemme, F. R., and Todd, M. J. (2005) Thermodynamicstability of carbonic anhydrase: measurements of binding affinity andstoichiometry using ThermoFluor®. Biochemistry 44, 5258-66) using thefollowing thermodynamic parameters of protein unfolding:

Reference RORγt T_(m): 47.8° C.

ΔH_((Tm))=115 kcal/mol

ΔC_(p(Tm))=3 kcal/mol

Cell Based Biological Data

RORγt Reporter Assay

A reporter assay was used to test functional activity of RORγtmodulatory compounds on transcriptional activation driven by the RORγtLBD. Cells used in the assay were co-transfected with two constructs.The first construct, pBIND-RORγt LBD, contained the wild type humanRORγt LBD fused to the DNA binding domain of the GAL4 protein. Thesecond construct, pGL4.31 (Promega Cat no. C935A), contained multipleGAL4 responsive DNA elements upstream of firefly luciferase. To generatea background control, cells were similarly co-transfected with twoconstructs, but in the first construct the AF2 amino acid motif in theRORγt LBD was changed from LYKELF (SEQ ID NO:5) to LFKELF (SEQ ID NO:6).The AF2 mutation has been shown to prevent co-activator binding to theRORγt LBD, thus preventing transcription of firefly luciferase. Themutant construct was called pBIND-RORγt-AF2.

For the RORγt constructs used in the reporter assay, numbering for thenucleotide sequences was also based on the reference sequence for humanRORγt, transcript variant 2, NCBI Accession: NM_001001523.1 (SEQ IDNO:1). For the wild type human RORγt LBD construct, pBIND-RORγt LBD,nucleotides 850-1635 (SEQ ID NO:2) coding for the wild type human RORγtLBD were cloned into EcoRI and NotI sites in the pBIND vector (Promegacat. No E245A). The pBIND vector contains the GAL4 DNA Binding Domain(GAL4 DBD) and the renilla luciferase gene under control of the SV40promoter. Renilla luciferase expression serves as a control fortransfection efficiency and cell viability. For the background controlconstruct, pBIND-RORγt-AF2, the AF2 domain of RORγt LBD was mutatedusing the Quik Change II Site Directed Mutagenesis System (StratageneCat. No. 200519). The nucleotide sequence coding for the RORγt LBDsequence with the mutated AF2 domain is shown as SEQ ID NO:7. The aminoacid sequences for the wild type RORγt LBD and RORγt LBD with themutated AF2 domain are shown as SEQ ID NO:8 and SEQ ID NO:9,respectively.

The reporter assay was performed by transiently transfecting HEK293Tcells with 5 μg of pBIND-RORγt LBD or pBIND-RORγt LBD-AF2 and 5 μgpGL4.31 (Promega Cat no. C935A) using Fugene 6 (Invitrogen Cat no.E2691) at a 1:6 ratio of DNA:Fugene 6 in a T-75 flask in which cellswere at least 80% confluent. Twenty four hours after bulk transfection,cells were plated into 96-well plates at 50,000 cells/well in phenol-redfree DMEM containing 5% Lipid Reduced FCS and Pen/Strep. Six hours afterplating, cells were treated with compounds for 24 hours. Media wasremoved and cells were lysed with 50 μL 1×Glo Lysis Buffer (Promega).Dual Glo Luciferase Reagent (50 μL/well) was then added and fireflyluciferase luminescence was read on an Envision after a ten minuteincubation. Finally, Stop and Glo reagent (50 IAL/well) was added andrenilla luciferase luminescence was read on an Envision instrument aftera ten minute incubation. To calculate the effect of compounds on RORγtactivity, the ratio of firefly to renilla luciferase was determined andplotted against compound concentration. Agonist compounds increaseRORγt-driven luciferase expression, and antagonist or inverse agonistcompounds decrease luciferase expression.

Human Th17 Assay

The human Th17 assay tests the effect of RORγt modulatory compounds onIL-17 production by CD4 T cells under conditions which favor Th17differentiation. Total CD4⁺ T cells were isolated from the peripheralblood mononuclear cells (PBMC) of healthy donors using a CD4⁺ T cellisolation kit II, following the manufacturer's instructions (MiltenyiBiotec). Cells were resuspended in a medium of RPMI-1640 supplementedwith 10% fetal bovine serum, penicillin, streptomycin, glutamate, andβ-mercaptoethanol and were added to 96-well plates at 1.5×10⁵ per 100 μLper well. 50 μL of compound at titrated concentrations in DMSO wereadded into each well at final DMSO concentration at 0.2%. Cells wereincubated for 1 hour, then 50 μL of Th17 cell differentiation medium wasadded to each well. The final concentrations of antibodies and cytokines(R&D Systems) in differentiation medium were: 3×10⁶/mL anti-CD3/CD28beads (prepared using human T cell activation/expansion kit, MiltenyiBiotec), 10 μg/mL anti-IL4, 10 μg/mL anti-IFNγ, 10 ng/mL IL1β, 10 ng/mLIL23, 50 ng/mL IL6, 3 ng/mL TGFβ and 20 U/mL IL2. Cells were cultured at37° C. and 5% CO₂ for 3 days. Supernatants were collected and theaccumulated IL-17 in culture was measured by using MULTI-SPOT® CytokinePlate following manufacture's instruction (Meso Scale Discovery). Theplate was read using Sector Imager 6000, and IL-17 concentration wasextrapolated from the standard curve. The IC50s were determined byGraphPad.

TABLE 1 RORγt RORγt reporter Human reporter Assay, % Th17 ExampleThermoFluor ® Assay, inhibition @ Assay, Number Assay, Kd (μM) IC50 (μM)6 μM IC₅₀ (μM)  1a ND ND ND ND  1b 0.13 0.16 89 0.4  1c 0.033 0.11 950.31  2a ND ND ND ND  2b 0.13 0.2 91 2.9  2c 0.14 0.17 95 0.67  3a ND NDND ND  3b 0.00056 0.003 96 0.013  3c 0.0023 0.0066 98 0.043  4a ND ND NDND  4b 0.0044 0.0095 98 0.061  4c 0.0014 0.011 98 0.031  5 0.62 1.7 87ND  6 0.94 1.9 92 ND  7a 0.072 >6 −60 ND  7b 0.037 >6 −78 >6  7c 0.77 >6−20 >6  8 0.27 0.89 87 ND  9a 0.068 0.27 90 ~0.9  9b 0.7 1.2 95 ND  9c0.032 0.31 96 ND 10 0.2 0.32 89 1.5 11 0.64 >6 32 ND 12 0.65 ~2 90 ND 132 >6 −52 ND 14a 0.0067 1.1 55 ND 14b 0.0052 0.24 53 0.079 14c 0.14 0.5187 0.31 15 0.021 >6 −29 ND 16 0.027 0.2 86 0.081 17 0.026 0.53 87 ND 18aND ND ND ND 18b 14 >6 40 ND 18c 0.33 0.85 95 ND 19a ND ND ND ND 19b 0.360.3 94 0.4 19c 0.017 >6 35 ND 20 ND ND ND ND 21a ND ND ND ND 21b 1.3 1.687 ND 21c 0.11 0.19 96 0.18 22 ND ND ND ND 23a ND ND ND ND 23b 15 ~4 60ND 23c 0.15 0.23 100 0.4 24 ND ND ND ND 25a ND ND ND ND 25b 3.5 ~2 87 ND25c 0.061 0.16 95 0.16 26 ND ND ND ND 27a ND ND ND ND 27b 15 ~4 80 ND27c 0.82 2.1 96 ND 28 0.046 0.024, ~0.04 96 ND 29 0.026 0.085 97 ND 30a0.023 0.11 91 ND 30b 0.3 0.049 95 0.057 30c 0.009 0.14 93 2.2 31a ND0.15 102 ND 31b 0.005 0.042 103 0.02 31c 3.3 1.6 85 ND 32a ND ND ND ND32b 0.77 1.2 92 ND 33a 0.16 0.65 98 ND 33b 13 ~4 64 ND 33c 0.077 0.13 990.29 34a ND ND ND ND 34b 0.45 1 90 ND 34c 0.1 0.27 96 0.26 35 0.018 0.16101 ND 36 0.00089 0.011, ~0.04 97 ND 37 0.0072 0.26 90 ND 38 0.000260.03 93 ND 39 0.0052 0.034 103 ND 40a 0.0015 0.023 104 ND 40b 0.15 0.6897 ND 40c 0.12 0.19 103 0.21 41a 0.089 0.32 98 ND 41b 0.0014 0.0086 1020.007 41c 0.0065 0.27 102 0.21 42 0.00051 0.017 103 ND 43 0.0035 0.03998 ND 44 5.4 >6 31 ND 45 0.77 0.57 93 ND 46 0.23 0.83 106 ND 47a 0.00830.04 98 ND 47b 0.93 ~2 80 ND 47c 0.0019 0.025 100 0.054 48 0.81 0.67 103ND 49a 0.1 0.22 104 ND 49b 10 ~5 71 ND 49c 0.065 0.23 100 0.28 50 0.090.031 99 ND 51 1.1 1.1 96 ND 52 3.5 ~6 52 ND 53 0.0072 ND ND ND 54 0.380.44 102 ND 55 3.3 ~3 70 ND 56 0.06 0.023 102 ND 57 0.58 0.69 100 ND 580.22 0.15 99 ND 59 1.2 0.54 98 ND 60a ND ND ND ND 60b 0.9 ~2 87 ND 610.45 0.13 105 0.48 62 0.057 0.12 110 0.1 63 0.0093 >6 26 ND 64 0.96 1 93ND 65 0.16 0.26 101 1.8 66 0.031 0.18 100 ND 67 0.0035 0.02 106 ND 680.0011 0.01 104 0.02 69 ND ND ND ND 70 ND ND ND ND 71 2.2 1.4 84 ND 720.89 0.63 100 ND 73 20 0.7 80 ~6 74 11 >6 60 ND 75 14 2.9 99 ND 76 18 ~280 ND 77 12 >6 48 ND 78 14 >6 33 ND 79 17 ND ND ND 80 12 >6 72 ND 81 14ND ND ND 82 11 >6 18 ND 83 15 1.9 73 ND 84 17 3.5 93 ND 85 20 3.5 81 ND86 20 >6 37 ND 87 12 >6 56 ND 88 20 >6 32 ND 89 10 >4 57 ND 90 ND ND NDND 91 21 >6 0 ND

All data shown in Table 1 is either the value of one data point or theaverage of more than one data point. In cases where more than one valueis shown in a table cell, values with qualifiers such as ˜, > or < shownon the right side of the table cell could not be included in theaveraging calculation for the value shown on the left side of the tablecell. ND—no data.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

All documents cited herein are incorporated by reference.

What is claimed is:
 1. A method for treating or ameliorating a RORγtmediated inflammatory syndrome, disorder or disease selected from thegroup consisting of: inflammatory bowel diseases, rheumatoid arthritis,psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis,ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma,multiple sclerosis, and systemic lupus erythematosus, comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I:

wherein: R¹ is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl,piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl,thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl,pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolol,and pyrazolol are optionally substituted with SO₂CH₃, C(O)CH₃, C(O)NH₂,CH₃, CH₂CH₃, CF₃, Cl, F, —CN, OCH₃, N(CH₃)₂, —(CH₂)₃OCH₃, SCH₃, OH,CO₂H, CO₂C(CH₃)₃, or OCH₂OCH₃; and optionally substituted with up to twoadditional substituents independently selected from the group consistingof Cl, OCH₃, and CH₃; and wherein said triazolyl, oxazolyl, isoxazol andthiazolyl are optionally substituted with one or two CH₃ groups; andwherein said azetidinyl is optionally substituted with CO₂C(CH₃)₃,C(O)NH₂, CH₃, SO₂CH₃, or C(O)CH₃; R² is 1-methyl-1,2,3-triazolyl,pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl,pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl,N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl,N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetylpiperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl,N—C₍₁₋₂₎alkyl-piperidinyl, thiazol-5-yl, 1-methyl imidazol-2-yl,1-(3-methoxypropyl)-imidazol-5-yl, or 1-C₍₁₋₂₎alkyl imidazol-5-yl;wherein said 1-C₍₁₋₂₎alkyl imidazol-5-yl is optionally substituted withup to two additional CH₃ groups, or one substituent selected from thegroup consisting of SCH₃, and Cl; and said pyridyl, and pyridyl-N-oxideare optionally substituted with up to two substituents independentlyselected from the group consisting of C(O)NH₂, —CN, OCH₃, CF₃, Cl, andCH₃; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionallysubstituted with up to two CH₃ groups; and said 1-methyl pyrazol-4-yl isoptionally substituted with up to two additional CH₃ groups; R³ is H,OH, OCH₃, NHCH₃, N(CH₃)₂ or NH₂; R⁴ is H, or F; R⁵ is H, Cl, —CN, CF₃,SCH₃, OC₍₁₋₃₎alkyl, OH, C₍₁₋₄₎alkyl, N(CH₃)OCH₃, NH(C₍₁₋₂₎alkyl),N(C₍₁₋₂₎alkyl)₂, NH-cyclopropyl, OCHF₂, 4-hydroxy-piperidinyl,azetidin-1-yl, or fur-2-yl; R⁶ is 2-chloro-thiophen-5-yl,1-methyl-pyrazol-4-yl, phenyl, pyrimidinyl, or pyridyl, wherein saidphenyl, pyrimidinyl, and pyridyl are optionally substituted with SO₂CH₃,NHSO₂CH₃, CF₃, F, Cl, —CN, OCH₃ or OCF₃; R⁷ is H Cl, —CN, C₍₁₋₄₎alkyl,OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃, SO₂CH₃, OCHF₂, NA¹A², C(O)NHCH₃,N(CH₃)CH₂CH₂NA¹A², OCH₂CH₂NA¹A², OCH₂CH₂NH₂, OC₍₁₋₃₎alkyl,OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl,pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl,1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted witha CH₃ group; A¹ is H or C₍₁₋₄₎alkyl; A² is C₍₁₋₄₎alkyl, cyclopropyl,C₍₁₋₄₎alkylOC₍₁₋₄₎alkyl, C₍₁₋₄₎alkylOH, C(O)C₍₁₋₂₎alkyl, or OCH₃; or A¹and A² may be taken together with their attached nitrogen to form a ringselected from the group consisting of:

R_(a) is H, F, OCH₃, or OH; R_(b) is CH₃, or phenyl; R⁸ is H, CH₃, OCH₃,or F; R⁹ is H, or F; and pharmaceutically acceptable salts thereof;provided that(4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-3-yl)methanamine,(4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol,(4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanamine,(4-chlorophenyl)(3-(2,6-dichlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,(4-chloro-3-phenylquinolin-6-yl)(2-(dimethylamino)pyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,4-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(l-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)thiomorpholine1,1-dioxide,1-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one,(2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol,(4-chloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol,(4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol,(2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol,6-((3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile,(2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-4-yl)(6-methylpyridin-3-yl)methanol,(4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol,(2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol, and(2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol areexcluded from the claim.
 2. The method of claim 1, wherein the diseaseis psoriasis.
 3. The method of claim 1, wherein the disease isrheumatoid arthritis.
 4. The method of claim 1, wherein the inflammatorybowel disease is ulcerative colitis.
 5. The method of claim 1, whereinthe inflammatory bowel disease is Crohn's disease.
 6. The method ofclaim 1, wherein the disease is multiple sclerosis.
 7. The method ofclaim 1, wherein the disease is neutrophilic asthma.
 8. The method ofclaim 1, wherein the disease is steroid resistant asthma.
 9. The methodof claim 1, wherein the disease is psoriatic arthritis.
 10. The methodof claim 1, wherein the disease is ankylosing spondylitis.
 11. Themethod of claim 1, wherein the disease is systemic lupus erythematosus.12. The method of claim 1, wherein the disease is chronic obstructivepulmonary disorder.
 13. A method of treating or ameliorating a syndrome,disorder or disease, in a subject in need thereof comprisingadministering to the subject an effective amount of a compound of claim1 or composition or medicament thereof in a combination therapy with oneor more anti-inflammatory agents, or immunosuppressive agents, whereinsaid syndrome, disorder or disease is selected from the group consistingof: rheumatoid arthritis, and psoriasis.